REVIEW

published: 01 November 2021

doi: 10.3389/fpls.2021.766509

The World of Algae Reveals a Broad

Variety of Cryptochrome Properties
and Functions
Jan Petersen 1†, Anxhela Rredhi 1†, Julie Szyttenholm 1†, Sabine Oldemeyer 2†,
Tilman Kottke 3,4† and Maria Mittag 1*†

 Matthias Schleiden Institute of Genetics, Bioinformatics and Molecular Botany, Friedrich Schiller University, Jena, Germany,
1

 Experimental Molecular Biophysics, Department of Physics, Freie Universität Berlin, Berlin, Germany, 3 Department of
2
Edited by:
Chemistry, Bielefeld University, Bielefeld, Germany, 4 Biophysical Chemistry and Diagnostics, Medical School OWL, Bielefeld
Margaret Ahmad,
University, Bielefeld, Germany
Université Paris-Sorbonne, France

Reviewed by:
Oren Levy, Algae are photosynthetic eukaryotic (micro-)organisms, lacking roots, leaves, and other
Bar-Ilan University, Israel
organs that are typical for land plants. They live in freshwater, marine, or terrestrial habitats.
Alfred Batschauer,
University of Marburg, Germany Together with the cyanobacteria they contribute to about half of global carbon fixation.
*Correspondence: As primary producers, they are at the basis of many food webs and they are involved in
Maria Mittag biogeochemical processes. Algae are evolutionarily distinct and are derived either by
[email protected]
primary (e.g., green and red algae) or secondary endosymbiosis (e.g., diatoms,
Specialty section: dinoflagellates, and brown algae). Light is a key abiotic factor needed to maintain the
This article was submitted to fitness of algae as it delivers energy for photosynthesis, regulates algal cell- and life cycles,
Plant Physiology,
a section of the journal and entrains their biological clocks. However, excess light can also be harmful, especially
Frontiers in Plant Science in the ultraviolet range. Among the variety of receptors perceiving light information, the
†
ORCID: cryptochromes originally evolved as UV-A and blue-light receptors and have been found
Jan Petersen,
in all studied algal genomes so far. Yet, the classification, biophysical properties, wavelength
orcid.org/0000-0002-8469-6679
Anxhela Rredhi, range of absorbance, and biological functions of cryptochromes are remarkably diverse
orcid.org/0000-0001-9787-7711 among algal species, especially when compared to cryptochromes from land plants
Julie Szyttenholm,
orcid.org/0000-0001-9373-0608 or animals.
Sabine Oldemeyer,
Keywords: blue-light receptor, Chlamydomonas, flavin, Ostreococcus, Phaeodactylum, photoreceptor,
orcid.org/0000-0001-7139-7218
photosynthetic microorganisms
Tilman Kottke,
orcid.org/0000-0001-8080-9579
Maria Mittag,
orcid.org/0000-0003-3414-9850 INTRODUCTION
Received: 29 August 2021
Accepted: 11 October 2021 What Are Algae?
Published: 01 November 2021 Algae are photosynthetic eukaryotes defined primarily by their lack of roots, leaves, and the
Citation: stem that are typical for higher plants (Parker et al., 2008). They are divided into microscopically
Petersen J, Rredhi A, Szyttenholm J, small microalgae that are a major part of phytoplankton and macroalgae, including seaweeds.
Oldemeyer S, Kottke T and Algae are found anywhere from soil to lakes, rivers and oceans and they are crucial to food
Mittag M (2021) The World of Algae
webs (Steele, 1974). Algal activities can even influence biogeochemical processes as observed
Reveals a Broad Variety of
Cryptochrome Properties and
with the Greenland ice sheet (McCutcheon et  al., 2021). Together with cyanobacteria, aquatic
Functions. algae are responsible for about 50% of global carbon fixation (Field et  al., 1998) and thus are
Front. Plant Sci. 12:766509. of high ecological relevance. Evolutionarily, algae can be  divided into two major groups, with
doi: 10.3389/fpls.2021.766509 one group derived from primary endosymbiosis and the other one from secondary endosymbiosis

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Petersen et al. Cryptochromes in the Algal World

(Keeling et al., 2005). For primary endosymbionts, a unicellular absorb strongly shifted from the well known red/far-red range
eukaryotic cell engulfed a cyanobacterium to become a to shorter wavelengths of visible light (Rockwell et  al., 2012).
chloroplast. In the case of secondary endosymbionts, a unicellular Moreover, new types of cryptochromes are present in algae
eukaryotic cell engulfed either a green alga (secondary green) with novel biophysical properties such as red-light absorption
or a red alga (secondary red). Recently, it was shown that and will be  detailed in the chapters below.
tertiary and possibly even higher-order endosymbiotic events Numerous photoreceptors are unique to algae. For example,
occurred (Sibbald and Archibald, 2020), but these will not aureochrome photoreceptors are only present in a single group
be  part of this review. Primary endosymbionts (named of algae, the photosynthetic stramenopiles, including
Archaeplastida) include glaucophytes (algae with cyanelle Xanthophyceae (yellow-green algae), diatoms, and brown algae
plastids), rhodophytes (red algae), chlorophytes (green algae), (Kroth et al., 2017). These aureochrome photoreceptors contain
and all land plants together with ferns and mosses (Bowman a light-oxygen-voltage (LOV) domain for light reception and
et  al., 2007; Adl et  al., 2012). Green algae and land plants a basic region leucine zipper (bZIP) domain for DNA binding
are also grouped as Chloroplastida. All these groups possess and act as light-driven transcription factors. In the green
plastids surrounded by two envelope membranes. In the lineages unicellular model alga Chlamydomonas reinhardtii (Cr), even
with secondary endosymbionts, plastids are encircled by either 18 different types of photoreceptors have been reported, including
four (e.g., diatoms, brown algae, haptophytes, and cryptophytes) two channelrhodopsins that are fundamental to its
or three membranes (euglenophytes, dinoflagellates; Gentil et al., photoorientation and several histidine kinase rhodopsins (HKRs)
2017). Some of these lineages still contain the nucleus of the whose functions are largely unknown (Greiner et  al., 2017;
engulfed green or red alga, but in a strongly reduced form, Luck and Hegemann, 2017). HKRs contain a His-kinase-,
called nucleomorph (e.g., in cryptophytes). Others such as response regulator-, and a rhodopsin domain. Some of the
euglenophytes, diatoms, dinoflagellates, or brown algae have HKRs even have guanylyl cyclase activity that has been recently
completely lost this nucleus (Gentil et al., 2017). In this review, used for application as an optogenetic tool (Tian et  al., 2021).
we  focus solely on algal groups with cryptochromes that have The field of optogenetics is self-evolving since knowledge on
been so far phylogenetically described based on existing genomes the exceptional properties of Cr channelrhodopsins became
or have been characterized by their photoreceptors. available (Hegemann and Nagel, 2013).
Further types of (possibly) novel light sensors were recently
discovered in phytoplankton in the open ocean (Coesel et  al.,
The Influence of Light on Algal Life and the 2021). The genomes of these marine microalgae encode light-
Diversity of Algal Photoreceptors sensing proteins with new combinations of known domain
Light is an important source of energy and information for structures or even fusions of different types of photoreceptors.
algal life on our planet (Figure  1). As for all photosynthetic For example, LOV domains were found within one protein
organisms, algae transform the radiation energy of the sunlight together with different DNA-binding domains such as a
into chemical energy (Eberhard et  al., 2008). They perceive homeobox or a heat shock factor domain or with signal-
light via pigments or specialized photoreceptors. Light regulates transduction motifs (e.g., an EF-hand; Coesel et  al., 2021). A
their photosynthesis and balances their photosynthetic new type of dual cryptochrome that is fused to another
apparatus, controls their behavior (photoorientation), entrains photoreceptor was also found in these genomes (Makita et  al.,
their circadian clocks, and influences their cell and sexual 2021) and is included in this review.
cycles as well as developmental processes (reviewed in It should also be  stated that the functions of photoreceptors
Hegemann, 2008; Kianianmomeni and Hallmann, 2014; Kottke in algae may differ from those in higher plants. For example,
et  al., 2017; Rredhi et  al., 2021). Cr phototropin influences the sexual cycle (Huang and Beck,
Cyanobacteria, also known as prokaryotic blue-green algae, 2003), the development of the eyespot, a primitive visual system
and eukaryotic algae have an amazing repertoire of different of the alga (Trippens et  al., 2012), and mediates the feedback
photoreceptors compared to land plants or animals. For many regulation of photosynthesis in the green alga (Petroutsos et al., 2016).
members, we  still do not know their detailed functions and/ Blue-light-activated adenyl cyclases represent another type
or mechanisms (Kianianmomeni and Hallmann, 2014; Greiner of light sensors in algae. They mediate photoavoidance in
et  al., 2017; Jaubert et  al., 2017; Kottke et  al., 2017; Kroth the secondary green alga Euglena gracilis (Iseki et  al., 2002)
et  al., 2017; König et  al., 2017b; Rockwell and Lagarias, 2020). and contain blue-light sensor using flavin adenine dinucleotide
In addition to the classically known photoreceptors from land (BLUF) domains (Ito et  al., 2010). In the green alga Cr as
plants which absorb in the red/far red (phytochrome) and well as in animal spermatozoa, the BLUF domain is directly
blue region of the visible spectrum (cryptochrome, phototropin, associated with dynein and involved in ciliary motility
Zeitlupe) as well as in the UV-B (UVR8; Kim et  al., 2007; (Kutomi et  al., 2021).
Fankhauser and Christie, 2015; Ahmad, 2016; Wang and Lin,
2020; Podolec et  al., 2021), algae bear several novel types of
light sensors. Moreover, cyanobacteria and algae also possess VARIETY OF ALGAL CRYPTOCHROMES
a larger variety of the above-mentioned “classical” photoreceptors
with new properties and biological functions. For example, In this review, we focus on the variety of cryptochromes found
cyanobacteriochromes, which are phytochromes in cyanobacteria, in algae. Cryptochromes are flavoproteins that were first described

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Petersen et al. Cryptochromes in the Algal World

FIGURE 1 |  Biological processes in algae that are regulated by light (reviewed in Hegemann, 2008; Kianianmomeni and Hallmann, 2014, Kottke et al., 2017; Sasso
et al., 2018). The description of the symbolized processes begins at the top of the scheme and moves in a clockwise manner: Photoorientation of flagellate algae:
tactic movement to the light is shown; phobic movement occurs with strong light (not shown). ǀ The algal circadian clock is entrained by light–dark cycles. ǀ The
sexual cycle of Chlamydomonas: vegetative cells turn into pregametes in the dark without a nitrogen source and then become gametes in the light in the absence of
a nitrogen source; gametes fuse and a resilient zygote is formed that needs a nitrogen source and light to undergo meiosis. ǀ Light is needed for photosynthesis and
influences the chloroplast architecture; thylakoid membranes are shown exemplarily (Rredhi et al., 2021) ǀ Light influences developmental processes in the
multicellular algae Saccharina and Volvox (Kianianmomeni and Hallmann, 2015; Yang et al., 2020). ǀ The cell cycle is symbolized; algal cells are synchronized by
light–dark cycles; M, mitosis; G1, gap1; S, synthesis; G2, gap2 (Coesel et al., 2009; Cross and Umen, 2015).

as blue-light receptors in plants and animals (Chaves et  al., (Chaves  et  al., 2011). The first cryptochromes were analyzed
2011). They are derived from the blue-light-dependent DNA as blue-light receptors in the land plant Arabidopsis thaliana
repair enzymes called photolyases that can be  found in pro- (At CRY1 and At CRY2; Ahmad and Cashmore, 1993, Chaves
and eukaryotes (Ahmad and Cashmore, 1993; Sancar, 2003; et  al., 2011) and in the fly Drosophila melanogaster (dCRY)
Chaves et  al., 2011). As primary light sensors, cryptochromes as an animal-type I  CRY (Emery et  al., 1998). Later, it was
and photolyases carry a non-covalently bound flavin adenine found that the cryptochromes from mice or humans group
dinucleotide (FAD) molecule within their photolyase homology to animal type II CRYs. They do not act as light sensors but
domain (PHR). Additionally, they may bind an antenna instead have a function in the central oscillator of the circadian
chromophore like 5,10-methenyltetrahydrofolate (MTHF) or clock (Okamura et  al., 1999; Todo, 1999; Chaves et  al., 2011).
8-hydroxy-7,8-didemethyl-5-deazaflavin (8-HDF). The antenna
chromophore harvests additional light and transfers the energy Cryptochrome Categories in Algae
to the FAD (Hoang et  al., 2008). Photoexcitation of the FAD To date, four different classes of cryptochromes are known in
may lead to a change of its redox state that can be  either algae based on phylogenetic analyses and further
oxidized (FADox), semireduced as an anion radical (FAD•−), characterizations. Moreover, a fifth class was recently described
semireduced as a neutral radical (FADH•) or fully reduced consisting of a fusion of a cryptochrome with another
(FADH−; Chaves et  al., 2011). Conformational changes are photoreceptor. The following section will present details on
promoted within the cryptochrome protein structure depending the five different classes:
on the FAD redox state, resulting in different signaling properties.
Most cryptochromes possess a C-terminal extension (CCT) 1. The classical plant cryptochromes (pCRYs) present in land
whose structure is rather undefined and only shows poor plants (At CRY1 and At CRY2) are found in some but not
conservation. The CCT varies in length depending on the in all algae. Plant CRYs, like all cryptochromes, share the
cryptochrome. Nevertheless, the CCT is of great importance conserved PHR at the N-terminus binding FAD (Chaves
for cryptochrome function and downstream signaling et  al., 2011), and contain a comparatively long CCT

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Petersen et al. Cryptochromes in the Algal World

(Reisdorph and Small, 2004; Müller et  al., 2017). Cr pCRY (Selby and Sancar, 2006; Pokorny et  al., 2008; Tagua et  al.,
has the longest known extension with about 500 amino 2015; Navarro et  al., 2020). Studies on repair activities by
acids (Figure  2). Plant CRYs may also bind MTHF as members of the cryptochrome/photolyase family in algal
antenna chromophore as derived from their homology to systems are rare. It was found that two out of three putative
CPD (cyclobutane pyrimidine dimer) photolyases (Chaves CRY-DASHs of the red picoalga Cm repair CPD lesions,
et  al., 2011; Beel et  al., 2012). There is no indication that but only in single-stranded and not in double-stranded DNA
pCRYs still have photolyase activity (Lin and Shalitin, 2003). (Asimgil and Kavakli, 2012). Interestingly, CRY-DASH
Plant CRYs are found in many investigated Chloroplastida proteins can be  located in organelles. The land plant At
(Figure  3) but seem to be  absent in the green picoalga CRY3 was found in the chloroplast and in mitochondria
Ostreococcus tauri (Ot), in the red macroalga Porphyra (Kleine et al., 2003), while the algal Cr CRY-DASH1 protein
umbilicalis (Pum) or in the diatom Phaeodactylum tricornutum was only found in the chloroplast (Rredhi et  al., 2021;
(Pt; Figure  3). Figure  2). Recently, algal CRY-DASHs were shown to
2. The cryptochrome–photolyase family (CPF1) of animal-like be  involved in further biological functions beside DNA
cryptochromes. For a long time, it was thought that all repair, supporting their additional or alternative role as
cryptochromes have lost photolyase activity. However, it was photoreceptors (Yang et  al., 2020; Rredhi et  al., 2021).
recently discovered that some algal animal-like CRYs from CRY-DASH proteins were found in all selected algal systems
Pt, Ot, and Cr have maintained photolyase activity (Coesel (Figure 3), including an Antarctic Chlamydomonas sp. ICE-L
et  al., 2009; Heijde et  al., 2010; Franz et  al., 2018). These in which its highest transcript expression level is at 5°C
animal-like cryptochromes group by their phylogeny closely and a salinity of 32% (Zhang et  al., 2020).
to the cryptochrome (6-4)–photolyase family (CPF1) and 4. The plant-like CryP, found in algae and metazoans. Instead
are thus phylogenetically located in between the animal-type of a classical pCRY, the genome of Pt encodes a plant-like
I  and -type II cryptochromes from animals (Beel et  al., CRY, named CryP (Juhas et  al., 2014; König et  al., 2017b)
2012). They exert further biological functions including light that was later identified in metazoan genomes (Oliveri et  al.,
perception and circadian clock control as well as the control 2014). CryP binds FAD and MTHF as chromophores and
of the algal Cr life cycle (Coesel et  al., 2009; Heijde et  al., has a CCT of about 70 residues (Figure 2). As in CRY-DASH
2010; Beel et  al., 2012; Zou et  al., 2017). Cr aCRY binds proteins, the FAD in CryP is present in the neutral radical
8-HDF as antenna chromophore (Franz et al., 2018; Figure 2). state after isolation as opposed to the oxidized state found
The CCTs of the animal-like CRYs are usually shorter as in pCRYs (see below; Juhas et  al., 2014). A plant-like CRY
compared to the pCRYs. Notably, CPF animal-like CRYs is also present in the picoalga Ot that lacks a classical pCRY.
are widely distributed in algae but are missing in land plants Interestingly, the red picoalga Cyanidioschyzon merolae (Cm)
(Figure  3). and the green picoalga Pycnococcus provasolii (Pp) have both
3. The CRY-DASH (Drosophila, Arabidopsis, Synechocystis, plant-like CRYs and plant CRYs (Figure  3).
Homo) cryptochromes. CRY-DASH (-like) proteins are found 5. Dualchrome, a new dual-photoreceptor chimera. Recently,
in many organisms from bacteria to vertebrates (Brudler a new type of photoreceptor from the marine picoalga Pp
et  al., 2003; Kiontke et  al., 2020). They group closely to was discovered in metagenome data of ocean picoplankton,
CPD photolyases (Beel et  al., 2012; Fortunato et  al., 2015). named dualchrome (DUC1, Figures  2, 3). DUC1 bears a
Bacterial, plant, and fungal CRY-DASHs can repair CPD fusion of a phytochrome and a plant CRY (Makita et  al.,
in single-stranded and even in double-stranded DNA, as 2021) and was not found in any other alga or other
reported for some members of the mucoromycotina fungi organisms so far.

FIGURE 2 |  Cryptochrome categories in algae (Juhas et al., 2014; Kottke et al., 2017; Makita et al., 2021; Rredhi et al., 2021). A representative member of each of
the five known categories is shown, starting with the classical plant cryptochrome of the green flagellate alga Chlamydomonas reinhardtii (Cr pCRY) and its long
C-terminal extension. It is followed by the Cr animal-like CRY of the cryptochrome/photolyase family (Cr aCRY), the Cr CRY-DASH1 with its chloroplast transit
peptide, the plant-like CryP of the diatom Phaeodactylum tricornutum and the dual cryptochrome DUC1 from the green picoalga Pycnococcus provasolii, a fusion of
a phytochrome and a cryptochrome. Domains are indicated, including the names of the chromophores (FAD) and antenna chromophores (MTHF, 8-HDF); FAD,
flavin adenine dinucleotide; MTHF, 5,10-methenyltetrahydrofolate; 8-HDF, 8-hydroxy-7,8-didemethyl-5-deazaflavin.

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Petersen et al. Cryptochromes in the Algal World

FIGURE 3 |  Cryptochrome distribution within selected algal species. Simplified schematic cladogram of cryptochrome (CRY) distribution within selected algal
species in comparison with the land plant Arabidopsis thaliana. Colored circles indicate the numbers (presented in each circle) and representatives of different types
of CRYs within the presented species (green, plant CRY; blue, plant-like CRY; orange, animal-like CRY/CPF1; purple, CRY-DASH and CRY-DASH-like; magenta,
dualchrome; gray, CRY(s) that are currently not assigned to the former groups; “?,” indicating that there may be further potential CRY(s) in this organism that have
not been identified so far). Information for the presented data was taken from the following references: Cyanidioschyzon merolae (Cm; Brawley et al., 2017),
Porphyra umbilicalis (Pum; Brawley et al., 2017), Saccharina japonica (Sj; Deng et al., 2012; Yang et al., 2020), Phaeodactylum tricornutum (Pt; Juhas et al., 2014;
Oliveri et al., 2014; Fortunato et al., 2015), Karenia brevis (Kb; Brunelle et al., 2007), Ostreococcus tauri (Ot; Heijde et al., 2010; Kottke et al., 2017), Pycnococcus
provasolii (Pp; Makita et al., 2021), Chlamydomonas reinhardtii (Cr; Beel et al., 2012; Kottke et al., 2017), Volvox carteri (Vc; Kottke et al., 2017) and Arabidopsis
thaliana (At; Chaves et al., 2011). Please note that three putative CRY-DASHs are predicted for Cm in the analysis of Asimgil and Kavakli (2012). For the genus
Karenia, three putative CRY/photolyase members are predicted (Shikata et al., 2019). The number of cryptochrome/photolyase members from an additional
dinoflagellate and from three stramenopile radiophytes, which all form noxious red tides (Shikata et al., 2019), has been omitted from the figure for clarity. As there is
no data available of CRYs from the secondary green line, this line was omitted. The cladogram was modified after Handrich et al. (2017).

Spatiotemporal Expression of Algal of green algal pCRYs (Müller et  al., 2017). In contrast to Cr
Cryptochromes pCRY, the Cr aCRY protein is rather consistently expressed
Expression Profiles in Light–Dark Cycles over the light–dark (LD) cycle (chosen cycle of 12 h light:12 h
The expression of algal cryptochromes was so far mainly studied darkness), being highest from the beginning until the middle
under light–dark cycles (diurnal conditions). In most cases, it of the day and lowest at the beginning of the night (change
is still unknown if their expression is also controlled by the in amplitude about 2-fold; Beel et  al., 2012; Kottke et  al., 2017).
circadian clock. Algal cryptochromes are routinely expressed in The third CRY from Cr, Cr CRY-DASH1 reaches its maximal
a diurnal way whereby the amplitude of the rhythm and the protein abundance at midday and is lowest at the beginning
phase of the peak can vary. The green algal Cr pCRY protein of the night (change in amplitude about 4-fold; Rredhi et  al.,
(formerly known as Chlamydomonas photolyase homolog 1, 2021). Taken together, the acrophases of peak expression vary
CPH1) is nearly absent during the day, but accumulates strongly with all three investigated Cr CRYs, ranging from early day
(amplitude increase up to tenfold) during the night (Reisdorph until late night. For some other algal cryptochromes, only
and Small, 2004; Müller et al., 2017). Cr pCRY protein abundance transcript abundances have been determined so far. In the kelp
seems to be  independent of the circadian clock (Müller et  al., Saccharina japonica (Sj), the maximum transcript level of a
2017). The protein is known to be  rapidly degraded by light CRY-DASH is reached at midday in a LD 12 h:12 h cycle (Yang
via the proteasome pathway. Transcript levels of Cr pCRY also et  al., 2020). Transcript levels of the marine picoalga Ot CPF1,
increase during the night (Kottke et  al., 2017), which is also as determined by microarrays, peak during the day, while levels
the case for a plant CRY from the chlorophyte Haematococcus of Ot CPF2, belonging to the CRY-DASH family, peak at the
pluvialis under the tested high light conditions (Hang et  al., beginning of the day (Heijde et al., 2010). Also in Pt, all studied
2020). These findings along with the negative regulation of Cr transcript levels of different CRYs (studied by qPCR) had rhythmic
pCRY in gametogenesis (see below) suggests a “dark” function expression in an LD cycle of 16 h:8 h with peaks in different

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Petersen et al. Cryptochromes in the Algal World

acrophases, indicating a possible functional diversification within cryptochromes. Like land plant CRYs, algal CRYs are involved
the diurnal cycle (Oliveri et  al., 2014). in the regulation of several cellular functions.

Localization of Cryptochromes Dual Function Cryptochromes: DNA Repair and

Depending on the expression and function, the subcellular More
localization of CRYs may vary. The green algal Cr aCRY plays The first evidence for an algal animal-like cryptochrome with
a role in vegetative cells as well as in pregametes and gametes repair activity came from a marine diatom. Pt CPF1 was found
(Zou et  al., 2017). During daytime (LD4 being 4 h after light to be  a member of the cryptochrome (6-4) photolyase family.
was switched on in a 12 h:12 h LD cycle), Cr aCRY is localized In contrast to other animal and land plant cryptochromes, Pt
to a significant extent in the nucleus of vegetative cells, but CPF1 shows (6-4) photoproduct repair activity (Coesel et  al.,
is mainly distributed over the cell body (most likely in the 2009). Using a Pt CPF1-overexpressing line, blue-light regulated
cytosol) at late night (LD22 being 10 h after light was switched transcript levels of wild type were compared to that line. The
off). In sexual cells (pregametes, gametes, and dark inactivated analyses suggest that Pt CPF1 has a regulatory role in controlling
gametes) Cr aCRY was never found in the nucleus, but always the photosynthetic light harvesting complex and photoprotection
distributed over the cell body. The presence of Cr aCRY in as well as cell-cycle progression in addition to its photolyase
the nucleus of vegetative cells at daytime is in congruence activity (Coesel et  al., 2009). Moreover, a clock function was
with its activity as (6-4) photolyase, repairing UV-B induced postulated as detailed in the section below. Similarly, Ot CPF1
damages (Franz et al., 2018). Thus, Cr aCRY localization varies from the marine picoalga Ot exerts (6-4) photolyase activity
depending on its function. In contrast, the subcellular localization and is involved in circadian rhythms (Heijde et  al., 2010). Also
of Pt CPF1  in the nucleus was not differentially regulated by the freshwater green alga Cr that lives mainly in wet soil (Sasso
darkness and light (blue or ultraviolet) treatment (Coesel et  al., 2018) has a dual function cryptochrome, Cr aCRY. It
et  al., 2009). repairs (6-4) photoproducts; a knockdown mutant is less resistant
For Cr pCRY, experimental data is lacking, but it is predicted to UV-B treatment than wild type (Franz et al., 2018). In addition,
to be  localized in the nucleus (Kottke et  al., 2017). aCRY is involved in regulating transcript levels that are controlled
In the case of the colony-forming alga Volvox carteri (Vc) by blue, yellow or red light, including those that encode a light
that consists of somatic cells and sexually active gonidia, harvesting protein (LHCBM6), glutamine synthetase 1, an enzyme
transcript levels were determined for different photoreceptors of nitrogen metabolism or the circadian clock component C3,
in the different cell types. Vc aCRY and Vc pCRY were found a subunit of the RNA-binding protein CHLAMY1 (Beel et al., 2012).
to accumulate during final cellular differentiation
(Kianianmomeni and Hallmann, 2015). Some Vc photoreceptor
Algal CRYs and the Biological Clock Machinery
genes, including Vc pCRY, are highly expressed in the somatic
As indicated above, dual function animal-like cryptochromes
cells. These data give first insights into the possibility that the
are also involved in the circadian clock machinery. For Pt and
different CRYs may also be  involved in developmental cycles.
Ot CPF1, the dual function was shown by positively testing
As mentioned above, CRY-DASH proteins like CRY3 from
their repressor activities in a heterologous system. The transcription
A. thaliana have been shown to be  localized in organelles;
factors CLOCK and BMAL were used for this purpose. They
CRY3 is found in chloroplasts and mitochondria (Kleine et  al.,
form a dimer and are part of the mammalian clock-controlled
2003). Localization studies revealed the presence of CRY-DASH
feedback loop. The inhibition of the CLOCK-BMAL-mediated
from the dinoflagellate Karenia brevis (Kb) only in chloroplasts
transcription by Pt and Ot CPF1 was positively verified in COS
(Brunelle et al., 2007). The green algal Cr CRY-DASH1 bearing
cells using an E-box bearing luciferase reporter system (Coesel
a chloroplast transit peptide was also found solely in the
et  al., 2009; Heijde et  al., 2010). Moreover, Ot CPF1 knockdown
chloroplast but not in mitochondria, using biochemical
lines were generated along with a luciferase reporter that was
fractionation (Rredhi et  al., 2021). Its localization is thus in
put under the control of a circadian promoter. In several of
close relation with its biological function, as detailed below.
these lines, period lengthening (of 1 up to 5 h) was observed
Localization of the novel type dualchrome was analyzed
compared to wild type, and the amplitude was dampened (Heijde
heterologously in tobacco cells in fusion with GFP. It was
et  al., 2010). In a Cr aCRY knockdown line, light-induced
primarily found in the nucleus and its localization was not
induction of the C3 subunit of the circadian RNA-binding protein
changed by light treatment (Makita et  al., 2021).
CHLAMY1 that influences the acrophase was altered (Beel et al.,
2012). These experiments suggest that dual function CPF1/aCRYs
Biological Functions of Algal play an important role within the circadian system.
Cryptochromes For the green algal Cr pCRY, an involvement in the circadian
Although a large repertoire of algal cryptochromes is known clock was also found, using knockdown lines and a representative
(Figure  3), only a few members have been studied in depth circadian clock-controlled process named photoaccumulation or
regarding their biological function(s). These studies were mostly phototaxis. Detection of this rhythm is automated (Forbes-Stovall
done in model algal species that can be transformed and where et  al., 2014; Müller et  al., 2017). Phase response curves (PRCs)
overexpressing lines and knockdown or knockout mutants can with blue-light pulses taken from wild type and a Cr pCRY
be  generated. Table  1 summarizes the main functions of these knockdown line revealed the influence of Cr pCRY on PRC

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Petersen et al. Cryptochromes in the Algal World

TABLE 1 |  Biological functions of algal CRYs, including comparative data from transgenic lines.

Type (6-4) (CPD) Circadian Sexual Photosynthesis: Other References

repair repair clock cycle Components,
apparatus

X X
● Cr pCRY Forbes-Stovall et al., 2014; Müller et al., 2017, Kamrani et al., 2018
● Pt CryP X Xa Juhas et al., 2014; König et al., 2017b
● Cr aCRY X X X X X Beel et al., 2012; Zou et al., 2017; Franz et al., 2018
● Pt CPF1 X X X X Coesel et al., 2009
● Ot CPF1 X X Heijde et al., 2010
● Ot CPF2 (CRY-DASH) X b
X Heijde et al., 2010
● Cr CRY-DASH1 X Xc Rredhi et al., 2021

a
Photoreceptor network;
b
weak CPD activity;
c
growth curve;
Cr, Chlamydomonas reinhardtii; Ot, Ostreococcus tauri, Pt, Phaeodactylum tricornutum.

behavior. The largest differences in phase resetting of about 10 h (germination). In this context, it is also of interest that blue
between wild type and the mutant were observed in early light is the main trigger for gamete formation and germination.
subjective night (Müller et  al., 2017). These data suggest a role However, red light also has a significant albeit smaller influence
of pCRY in the entrainment of the circadian clock. Moreover, on germination (Zou et  al., 2017). aCRY with its property to
the Cr pCRY knockdown line exerts a significantly lengthened absorb also in the red spectral region in addition to blue (Beel
period of about 27.9 h compared to wild type (24.5 h in average); et  al., 2012, see also chapter on properties below) seems to
it becomes arrhythmic after a few days under free-running be the relevant receptor for red light because pCRY and phototropin
conditions that are used to analyze clock properties. It was also do not absorb in this range.
suggested that pCRY positively regulates the clock component,
ROC75, a putative transcription factor (Kamrani et  al., 2018). CRYs and the Photosynthetic Apparatus
These data support the model that Cr pCRY is not only involved Regulation
in circadian input but is also linked to the central oscillator. CRYs have a broad influence on the photosynthetic machinery
by regulating transcript levels and/or protein abundance of
CRYs and Life Cycle Regulation photosynthetic components, pigments or the entire photosynthetic
The sexual cycle of the unicellular alga Cr, which is regulated machinery. Here, we  will present exemplarily the effects of
by light and nitrogen availability [reviewed in Kottke et  al. two representative CRYs, the plant-like CryP from Pt and
(2017); Sasso et  al. (2018)], is well studied. Cr vegetative cells CRY-DASH1 from Cr, but it should be  mentioned that also
of both mating types (mt+ and mt−) turn into pregametes in Pt CPF1 and Cr aCRY were shown to be  involved in the
the dark upon the removal of the nitrogen source. In the presence regulation of transcript levels of photosynthetic compounds
of light and without nitrogen source, pregametes become gametes. (Coesel et  al., 2009; Beel et  al., 2012).
This process is controlled by three photoreceptors. It is promoted Plastids and the photosynthetic apparatus of diatoms are
by phototropin and inhibited by two algal cryptochromes, aCRY different from that of Chloroplastida in several aspects.
and pCRY (Huang and Beck, 2003; Müller et  al., 2017; Zou Diatoms belong to the secondary red endosymbionts
et  al., 2017). It is assumed that the inhibition process allows (Figure 3). Their plastids are surrounded by four membranes,
gametes to reconvert to pregametes and vegetative cells if a and they possess additional fucoxanthin pigments that give
nitrogen source becomes available short term. Sexually active them an orange, brownish color. Based on a Pt CryP knockdown
gametes finally fuse to form a quadriflagellated cell that is line, effects of this plant-like CRY on proteins of the
converted to a resilient zygote (Figure  1). Zygotes can survive photosynthetic apparatus were studied. Here, the most
in the dark and without a nitrogen source for months (Sasso prominent members of the diatom light harvesting chlorophyll-
et  al., 2018). Upon light and nitrogen availability, germination fucoxanthin family (Lhcf) as well as proteins involved in
is induced, and a tetrad of haploid vegetative cells is formed their photoprotection (Lhcx) were analyzed. Lhcf1 -Lhcf11
which results in individual vegetative cells. Activation of protein abundance was enhanced in the CryP knockdown
germination is again mediated by the above-mentioned three strains in comparison to wild type cells (Juhas et  al., 2014).
photoreceptors (phototropin, aCRY, and pCRY), but in this case Contrarily, the protein level of Lhcx was decreased in the
all three act in concert as positive regulators (Huang and Beck, knockdown lines (Juhas et  al., 2014). Changes were also
2003; Müller et  al., 2017; Zou et  al., 2017). Thus, both aCRY observed in transcript levels under slightly different conditions,
and pCRY play central roles in the sexual cycle of Cr either but were not always in agreement with the protein levels
as negative regulators (gamete formation) or as positive regulators suggesting that posttranscriptional regulation plays a role

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Petersen et al. Cryptochromes in the Algal World

(König et  al., 2017a). Taken together, these data show that photochemical reaction. This reaction causes a change in
CryP contributes significantly to changes in photosynthetically structure and/or conformation of the protein, which then may
relevant compounds. change the interaction of the receptor with a signaling partner
Characterization of the green algal Cr CRY-DASH1 protein such as a specific binding protein or DNA. Finally, a signal
represents a first functional in-depth study of an algal CRY-DASH transduction cascade leads to a change in the physiology of
protein. The Cr CRY-DASH1 knockout line showed a significantly cells and organisms.
reduced growth rate (Rredhi et  al., 2021) in contrast to Pt
CryP knockdown lines that were influenced in photosynthesis
components, but had a similar growth rate to wild type (Juhas Light-Induced Oligomerization of Cryptochromes
et  al., 2014). Intriguingly, the content of chlorophyll a and b An interesting aspect of the cryptochrome response to light
as well as of the carotenoids was increased in the CRY-DASH1 is that the photochemical reaction of the FAD may cause a
knockout line. This was even visible by the naked eye; cultures change in the oligomerization state, i.e., in the number of
of the knockout line were of a darker green than wild type identical receptors that associate within a dynamic complex.
(Rredhi et  al., 2021). The increase in pigments went hand in A formation of large complexes called photobodies of At CRY2
hand with hyper-stacking of thylakoid membranes and an has been observed in plant cells (Mas et  al., 2000), which is
increase in two of the central proteins of photosystem II, D1 in agreement with a homooligomerization to clusters of receptors
and the antenna protein CP43  in the mutant line (Rredhi upon blue-light illumination (Bugaj et al., 2013). These clusters
et al., 2021). CRY-DASH1 thus acts as a repressor that prevents are reversible in the dark and dissociate within minutes.
the synthesis of excessive pigments and membranes and thus Accordingly, the reversible clustering has drawn much attention
balances the photosynthetic machinery. Its regulatory role seems to the development of optogenetic tools to localize fusion
to be  exerted at the posttranscriptional/translational level as proteins to one spot within mammalian cells by illumination
the transcript levels of the genes encoding D1 and CP43 are (Bugaj et  al., 2013; Taslimi et  al., 2014). Recent structural
not altered in the mutant compared to wild type (Rredhi et al., characterization by cryo-electron tomography and X-ray
2021). It is postulated that the observed reduction in growth crystallography has revealed that At CRY2 forms tetramers of
is due to the higher pigment amount resulting in a shading the PHR upon illumination (Ma et  al., 2020; Shao et  al., 2020;
effect. Indeed, light intensity within a culture flask of the Palayam et  al., 2021).
knockout line was reduced compared to that of a wild-type- Oligomerization of algal cryptochromes has been studied
containing-flask (Rredhi et al., 2021). Notably, Cr CRY-DASH1 on some selected members and light-induced changes in
absorbs primarily in the UV-A range (see chapter below), oligomerization have been found. A similar clustering behavior
where the photosynthetic pigments absorb only to a to At CRY2 has been observed for the light-sensitive domain
smaller extent. of algal Cr pCRY as a fusion protein labeled with a fluorescence
protein. The light-induced degradation of Cr pCRY in C.
Others reinhardtii prevents a study of a potential functional role of
The recently described dualchrome (DUC1) represents a chimera this clustering in vivo (Reisdorph and Small, 2004; Müller
consisting of a phytochrome and a cryptochrome in the rather et  al., 2017). However, it has been shown that a complex
unknown green picoalga Pp (Figure  2). It was found that the containing Cr pCRY is formed at the end of the night in C.
Pp genome encodes also further homologue proteins of the reinhardtii, possibly in context with its dark-related function.
model plant A. thaliana involved in light signaling such as It remains open whether this complex includes homooligomers
phototropin, CONSTITUTIVE PHOTOMORPHOGENIC 1 of pCRY or if it is a heteromeric complex with yet unknown
(COP1), or ELONGATED HYPOCOTYL 5 (HY5) in addition partner(s) (Müller et  al., 2017).
to the mentioned CRY variants (Figure  3). Thus, it possesses The oligomerization state has been characterized for isolated
a gene set necessary for adapting to various light conditions Cr aCRY in great detail. Here, red light induces the transition
(Makita et  al., 2021). from a dimer in the dark to a tetramer in the light (Oldemeyer
The presence of several CRYs and other photoreceptors et  al., 2016). Interestingly, the presence of the CCT is required
in algae elicits the question of if they form a photoreceptor for the formation of the dimer in the dark. Truncation of the
network influencing each other. Indeed, it was found in Pt CCT produces a monomer, which forms a dimer upon
CryP knockdown lines that the transcript levels of other illumination only to a small extent (Oldemeyer et  al., 2016).
photoreceptors (Pt phytochrome and Pt CPF1) are influenced Some deviating results on oligomerization states of Cr aCRY
by the reduction of Pt CryP. These data suggest exactly such can be  explained by the different exclusion volumes of the
a scenario (König et  al., 2017a). columns used for gel filtration (Franz-Badur et  al., 2019).
In summary, light-induced changes in oligomerization state
have been observed in algal cryptochromes but differ between
Biophysical Properties of Algal pCRY and aCRY. In general, little is known about complex
Cryptochromes formation of algal cryptochromes with signaling partners or
The physiological responses to light are the result of a chain other photoreceptors. These signaling partners need to
of events on the molecular level. First, light is absorbed by a be  identified to link the changes in oligomerization state to
chromophore bound to the receptor, which then leads to a the signal transduction cascade.

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Petersen et al. Cryptochromes in the Algal World

Strong Variations in the Absorption

Spectra Define the Different Roles of Algal A
Cryptochromes
The absorption spectrum of a photoreceptor in the dark is
decisive for the region of the sun’s spectrum, by which this
receptor is activated. Ideally, the absorption spectrum matches
the action spectrum that was recorded for the function in
vivo. The absorption spectrum of cryptochromes reflects the
redox state of the FAD cofactor, i.e., whether it binds oxidized
FAD (FADox), the anion radical (FAD•−), the neutral radical
(FADH•), or fully reduced FAD (FADH−). Different redox states
of FAD can be  stabilized in the dark by the specific protein
environment of a cryptochrome. Accordingly, a cryptochrome
acts as a blue and UV-A light receptor, if (FADox) is the stable
redox state in the dark.
The interpretation of the absorption spectra of cryptochromes
is complicated by the fact that usually the recording is performed
after isolation from a heterologous expression system, which
might lead to an oxidation of the FAD. In addition, an antenna
chromophore is bound to some cryptochromes, which might
be  lost upon purification or might not even be  produced by
the heterologous expression system. The antenna molecule,
B
which has a higher extinction coefficient as compared to flavin,
serves the purpose to absorb the light and to transfer energy
to the FAD cofactor, thereby increasing the probability of
light absorption.
The plant cryptochrome Cr pCRY shows a typical spectrum
for a blue-light receptor carrying oxidized FAD (FADox) with
maxima in the blue and UV-A region (Figure  4A; Immeln
et  al., 2007). The presence of the CCT does not influence
the absorption spectrum (Goett-Zink et  al., 2021). Some FIGURE 4 |  Absorption spectra of different cryptochromes from algae
recorded in vitro directly after isolation and the postulated roles of the redox
residual MTHF has been identified after purification from
states of FAD in these cryptochromes. (A) The absorption spectra of
bacterial cells, but a functional role as an antenna chromophore cryptochromes are characterized by the different oxidation states of the FAD
and binding of MTHF in the alga is not likely. FADox in chromophore and the binding of antenna molecules. The plant cryptochrome
pCRY is even present in the strongly reducing cytosol of Cr pCRY binds FADox and acts as blue-light receptor. Plant-like cryptochrome
living Escherichia coli cells (Goett-Zink et  al., 2021), which Pt CryP and animal-like cryptochrome Cr aCRY both absorb almost in the full
visible spectral region because of the absorption of FADH•. However, Pt CryP
is a strong argument for FADox being the native chromophore binds MTHF as antenna, whereas Cr aCRY binds 8-HDF leading to different
of pCRY in Chlamydomonas in the dark similar to findings absorption maxima in the UV-A and blue region, respectively. The UV-A-
for pCRYs from land plants (Bouly et  al., 2007). receptor Cr CRY-DASH1 absorbs mainly at around 380 nm dominated by the
Members of the animal-like CRY/CPF1 family such as contribution of MTHF, whereas its chromophore FADH− absorbs only weakly.
For simplicity, the absorption of FADox, FADH• and FADH− is indicated at the
Ot CPF1, Pt CPF1 and Cr aCRY bind FADox after purification
maximum with highest wavelength, but all FAD species also contribute to the
(Coesel et  al., 2009; Heijde et  al., 2010; Beel et  al., 2012). absorption at lower wavelengths. Spectra were displaced vertically for better
The more unusual was the finding that Cr aCRY uses the visibility. (B) The redox states of FAD play different roles in the algal
flavin neutral radical (FADH•) as the dark state for a sensory cryptochromes, as postulated on the basis of the absorption spectra and
function thereby accessing almost the complete visible spectral functional studies of representative members. The dark form indicates the
redox state present in vivo in the dark. Light absorption induces a reduction of
region including yellow and red light (Beel et  al., 2012;
the FAD. The signaling state is associated with conformational changes and/or
Figure 4A). This fact suggests that FADH• is the predominant changes in oligomerization state of the receptor that drive signal transduction.
form of FAD in the alga in the dark, which is supported
by a very efficient photoactivation reaction from FADox to
FADH• in vitro (Lacombat et  al., 2019). The tight binding
of an antenna molecule is another difference of aCRY/CPF1 the FADH• in the dark, preventing oxidation (Oldemeyer
to plant cryptochromes. The binding of 8-HDF was suggested et  al., 2020).
for Ot CPF1 from structural considerations (Brazard et  al., Much less is known about the plant-like subfamily and its
2012) and then identified for Cr aCRY after implementing member Pt CryP. The binding of stable FADH• and MTHF
the synthesis of 8-HDF in E. coli (Franz et  al., 2018). The in the dark after purification might indicate a light response
antenna 8-HDF strongly absorbs light in the blue region of similar to the aCRY family, with the distinct difference that
the visible spectrum (Figure  4A) and additionally stabilizes the antenna MTHF absorbs shifted to the UV-A region compared

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Petersen et al. Cryptochromes in the Algal World

to 8-HDF (Figure  4A; Juhas et  al., 2014). Functional studies be  to analyze the role of all these photoreceptors and their
have focused so far only on the blue-light effects of CryP on mutual interaction partners in the in vivo systems.
Pt physiology (König et al., 2017a). It would be of high interest Algae represent a rich source for novel cryptochrome
to study also potential responses of Pt CryP to green and photoreceptors. These might be  used as optogenetic tools to
red light. generate light switches in algal cells for controlling gene
The large subfamily of CRY-DASH proteins (Brudler et  al., expression or in combination with signaling molecules such
2003) is also well represented with several members in algal as cAMP or Ca2+ (Kianianmomeni and Hallmann, 2014).
genomes (Figure  3). Few members have been isolated and They might trigger light-dependent adaptations of organismal
characterized by absorption spectroscopy. A typical behavior physiology, development, and behavior in nature (Losi et  al.,
for members of CRY-DASH has been found for Ot CPF2 in 2018) and thus create potent tools for biotechnological
vitro, which showed a dominant absorbance by the antenna approaches. They may also be  used in heterologous systems
MTHF and some contribution from FADox (Heijde et  al., for neurobiology and in medicine, as it was recently done
2010). Similar findings have been presented for Cm PHR5 with an algal rhodopsin to partly recover vision in blind
(Asimgil and Kavakli, 2012). Recent investigations on Cr people (Sahel et  al., 2021). The land plant At CRY2 was
CRY-DASH1 revealed that FAD is present in the fully reduced already used for optogenetical protein clustering (Park et  al.,
state (FADH−) directly after purification, which together with 2017) and for regulating gene expression in mammalian cells
the photochemical results indicates a presence of FADH− in (Hernández-Candia et  al., 2019). In general, the high variety
Cr in vivo (Rredhi et  al., 2021). As a result, Cr CRY-DASH1 of algal CRYs offers a high potential for engineering new
mainly absorbs light in the UV-A-region (Figure 4A), supported sensor tools.
by functional studies as a UV-A receptor in Cr. Of note, Currently, we are only beginning to understand the biophysical
the UV-A absorption of CRY-DASH1 is maximal in a spectral properties and the involved signal transduction pathways as
region where the typical blue-light receptors pCRY and well as the biological functions of the different algal
phototropin as well as photosystems I  and II show only weak cryptochromes. Their interplay within one algal system and
absorption. Accordingly, CRY-DASH1 may complement the along with the other photoreceptors of this system remains
other receptors in the alga by the spectral range in which largely enigmatic, even in the today selected model algal
it is activated. organisms. Double-, triple-, or even higher-order mutants need
In summary, the strong differences in the absorption spectra to be  produced to gain further insights in their complex
of cryptochromes in the dark reflect the variety of functions photobiology. Yet, the basis of these light signaling events is
for which these receptor subfamilies evolved (Kottke et al., the key to understand (i) algal fitness and thus (ii) their central
2017; Figure 4B). Cryptochromes act in algae as UV-A receptor contribution as photosynthetic organisms to life on Earth. As
(Cr CRY-DASH1), as UV-A/blue-light receptor (Cr pCRY) our knowledge on the role and function of algal cryptochromes
and as “white light” receptor covering almost the full spectral improves, it will be possible to manipulate growth, reproduction
region (Cr aCRY), defined by the redox state of FAD cofactor and the development of algae as well as to optimize
in the dark. The FAD is reduced after the absorption of light photosynthesis, for example by application of targeted
and forms the signaling state, accompanied by conformational illumination protocols.
changes and/or changes in oligomerization state of the receptor.
The identification of the signaling state and the mechanism
of signal propagation within the receptor are important AUTHOR CONTRIBUTIONS
biophysical questions to be  answered for each member. The
details of the different pathways identified to date go beyond JP, AR, JS, and MM designed and drew Figures  1–3. SO and
the scope of this review. Even more differences in the light TK created Figure  4. JP and MM arranged Table  1. JP, AR,
responses will be  revealed as more and more candidates of TK, and MM wrote the paper, with input from all authors.
algal cryptochromes are being characterized biophysically. All authors contributed to the article and approved the
submitted version.

OUTLOOK
FUNDING
It is expected that metagenome analysis from phytoplankton
will lead to the discovery of even more novel types of Our work was supported by the Deutsche Forschungsgemeinschaft
photoreceptors, including new cryptochrome variants such as by DFG grants Mi373/16-1 to MM and Ko3580/4-2 and Ko3580/7-1
the recently identified DUC1. The high number of different to TK. SO was funded by the DFG Sonderforschungsbereich SFB1078.
light sensors in aquatic organisms is correlated with the fact
that light quality and light quantity for aquatic algae change
dynamically. The light conditions depend on the depth within ACKNOWLEDGMENTS
the water column where the algae occur at a given time in
the ocean, on the presence of solved particles and on other We thank Claudia Büchel, Ellen McPherson and the referees
light-absorbing organisms at this location. The challenge will for helpful comments on the review.

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Petersen et al. Cryptochromes in the Algal World

Fankhauser, C., and Christie, J. M. (2015). Plant phototropic growth. Curr.

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