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© 2014. Published by The Company of Biologists Ltd | Development (2014) 141, 2921-2923 doi:10.1242/dev.108407
SPOTLIGHT
The POU-er of gene nomenclature
ABSTRACT
The pluripotency factor POU5F1 (OCT4) is well known as a key
regulator of stem cell fate. Homologues of POU5F1 exist throughout
vertebrates, but the evolutionary and functional relationships between
the various family members have been unclear. The level to which
function has been conserved within this family provides insight into
the evolution of early embryonic potency. Here, we seek to clarify the
relationship between POU5F1 homologues in the vertebrate lineage,
both phylogenetically and functionally. We resolve the confusion over
the identity of the zebrafish gene, which was originally named pou2,
then changed to pou5f1 and again, more recently, to pou5f3. We
argue that the use of correct nomenclature is crucial when discussing
the degree to which the networks regulating early embryonic
differentiation are conserved.
Class V POU (POUV) transcription factors are important regulators
of potency, differentiation and early development in vertebrates.
They constitute one of five classes of POU domain-containing
proteins defined by similarity within both the homeodomain and the
POU-specific domain (Rosenfeld, 1991). Mouse POU5F1 (also
called OCT3 or OCT4) was the first class V member identified
(Lenardo et al., 1989; Okamoto et al., 1990; Rosner et al., 1990;
Schöler et al., 1989, 1990). It is a central regulator of embryonic
stem cell (ESC) pluripotency (Nichols et al., 1998; Niwa et al.,
2000; Yuan et al., 1995) and the most essential of the four factors
originally identified as being able to induce reprogramming of
somatic cells to induced pluripotent stem cells (iPSCs) (Takahashi
and Yamanaka, 2006; Yu et al., 2007). Since the initial
characterisation of POU5F1, homologues have been identified in
many vertebrates, including frog, chicken, axolotl, teleost fishes and
sturgeon.
As more POUV genes were identified, it became apparent that the
POUV family has a complex evolutionary history. Some eutherian
mammals possess a second, single-exon POUV gene, POU5F2
( previously called SPRM-1), which has a role in spermatogenesis
(Andersen et al., 1993; Pearse et al., 1997) and presumably arose in
1
Department of Zoology, University of Melbourne, Melbourne, VIC 3010, Australia.
Department of Biochemistry, The Rappaport Family Institute for Research in the
Medical Sciences, Faculty of Medicine, Technion - Israel Institute of Technology,
3
Haifa 31096, Israel. University of California Berkeley, Department of Molecular &
Cell Biology, 142 Life Sciences Addition # 3200, Berkeley, CA 94720-3200, USA.
4
School of life Sciences, University of Nottingham, Queen’s Medical Centre,
5
Nottingham NG7 2UH, UK. Wellcome Trust - Medical Research Council Stem Cell
Institute, University of Cambridge, Tennis Court Road, Cambridge CB2 1QR, UK.
6
Laboratory for Pluripotent Stem Cell Studies, RIKEN Center for Developmental
Biology (CDB), 2-2-3 Minatojima-minamimachi, Chuo-ku, Kobe 6500047, Japan.
7
Max Planck Institute for Molecular Biomedicine, Rö ntgenstraße 20, Mü nster 48149,
8
Germany. DFG Research Center for Regenerative Therapies – CRTD, Technische
9
Universitä t Dresden, Fetscherstrasse 105, Dresden 01307, Germany. Division of
Developmental Biology, Cincinnati Children’s Hospital Medical Center, 3333
10
Burnet Ave, Cincinnati, OH 45227, USA. The Danish Stem Cell Centre (DanStem),
University of Copenhagen, Blegdamsvej 3B, Copenhagen N DK-2200, Denmark.
2
*Authors for correspondence ([email protected]; [email protected])
an ancestral eutherian by retroviral insertion of a copy of POU5F1.
Marsupial and monotreme genomes contain two POUV genes:
POU5F1 and another homologue now called POU5F3. Both the
marsupial POUV genes (POU5F1 and POU5F3) are expressed in
early development in domains similar to those described for Pou5f1
in the mouse (Frankenberg et al., 2010, 2013). Notably, some
vertebrate lineages have orthologues of both POU5F1 and
POU5F3, whereas others (including eutherian mammals) have
only POU5F1 and others only POU5F3 (Fig. 1). The basis for this
pattern of evolution is unclear, but is possibly due to distinct roles
for each paralogue that became redundant in a taxon-specific
manner.
In zebrafish, a POUV gene was identified and originally, albeit
confusingly, named pou2 (Takeda et al., 1994). With the availability
of the complete sequence, it became clear that pou2 encodes a class
V POU protein (Burgess et al., 2002) and, based on an assumption
of orthology with mammalian POU5F1 (Lunde et al., 2004),
zebrafish pou2 was subsequently renamed pou5f1. However, the
zebrafish gene is not a true orthologue of mammalian POU5F1 but
is instead more closely related to mammalian POU5F3, as indicated
by conservation of both synteny and sequence (Frankenberg et al.,
2010; Frankenberg and Renfree, 2013; Niwa et al., 2008; Tapia
et al., 2012). Moreover, a recent study (Frankenberg and Renfree,
2013) has now demonstrated unequivocally that the gene
duplication event giving rise to POU5F1 and POU5F3 occurred
before the divergence of extant cartilaginous and bony fishes,
showing conclusively that the zebrafish gene is a true POU5F3
orthologue. On the weight of this evidence, the Zebrafish
Nomenclature Committee re-renamed the zebrafish gene pou5f3,
reflecting its proper place in the POUV family. We now support the
application of this nomenclature to all vertebrate orthologues of
POU5F3 (see Table 1).
The degree to which the function of the POUV proteins is
conserved in evolution is variable. This has been tested by the
capacity of different POUV proteins to rescue the loss of
endogenous POU5F1 activity in ESC self-renewal (Hammachi
et al., 2012; Morrison and Brickman, 2006) or in the generation
of iPSCs (together with three other mammalian factors) (Tapia
et al., 2012). Based on these assays, orthologues of POU5F1 and
POU5F3 show varying degrees of functional conservation in
inducing pluripotency and supporting self-renewal. In particular,
in Xenopus, which has three POU5F3 genes ( pou5f3.1, pou5f3.2
and pou5f3.3) that presumably arose by tandem duplication, the
expression pattern and activity of these genes have diversified
such that only one of them – pou5f3.1 – is expressed in primordial
germ cells and has ‘OCT4-like’ activity in both reprogramming
and ESC self-renewal (Livigni et al., 2013; Venkatarama et al.,
2010; Tapia et al., 2012). Other POU5F3 genes, including the two
other Xenopus genes, have varying degrees of OCT4-like activity
in such assays, but it is notable that zebrafish pou5f3 has little
activity in either reprogramming or the support of Pou5f1 mutant
ESCs (Lavial et al., 2007; Morrison and Brickman, 2006; Niwa
2921
DEVELOPMENT
Stephen R. Frankenberg1,*, Dale Frank2, Richard Harland3, Andrew D. Johnson4, Jennifer Nichols5,
Hitoshi Niwa6, Hans R. Schö ler7, Elly Tanaka8, Chris Wylie9 and Joshua M. Brickman10, *
SPOTLIGHT
Development (2014) 141, 2921-2923 doi:10.1242/dev.108407
et al., 2008; Tapia et al., 2012). Zebrafish pou5f3 also participates
in zygotic genome activation (Lee et al., 2013; Leichsenring et al.,
2013) and, although this has not been explored in mammals, the
observation that mouse embryos develop to the blastocyst stage in
the absence of both maternal and zygotic Pou5f1 (Frum et al.,
2013; Le Bin et al., 2014; Nichols et al., 1998; Wu et al., 2013)
suggests that this function might not be conserved. Although there
is a degree of redundancy in function between POU5F1 and
POU5F3, as is particularly evident from species that have lost one
of these genes, this is not always the case. Understanding the
relationship between the evolution of this family and the degree to
which the network regulating pluripotency is conserved requires
an unambiguous representation of the phylogenetic relationships
through nomenclature.
Despite clear evidence that the zebrafish POUV gene is a
POU5F3 orthologue, and the recent renaming of the gene to reflect
this, the name pou5f1 is still persistently used in the literature
(Bensch et al., 2013; Kotkamp et al., 2014; Lee et al., 2013;
Leichsenring et al., 2013; Lippok et al., 2014; Rodriguez-Mari et al.,
2013). Onichtchouk (2012) had argued that, because the duplication
event giving rise to the two mammalian paralogues was not proven
to pre-date the divergence of tetrapod and teleost lineages, pou5f1 is
a valid name for the zebrafish gene despite it being more similar to
mammalian POU5F3 than to mammalian POU5F1. However, a
subsequent study (Frankenberg and Renfree, 2013) demonstrated
unequivocally that the duplication event occurred before the
divergence of extant cartilaginous and bony fishes. Clearly,
the use of the correct name does not alter the underlying biology
or the degree to which pluripotency is or is not conserved in teleosts.
However, the use of common names for orthologous genes is
Table 1. The presence/absence and synonyms of POU5F1, POU5F2 and
POU5F3 in selected vertebrates
Taxon
POU5F1
POU5F2
(OCT3/OCT4) (SPRM-1)
POU5F3 previous
POU5F3 name(s)
Eutherians
Marsupials
Monotremes
Birds
Xenopus
✓
✓
✓
×
×
✓
×
×
×
×
Salamanders
Teleost fishes
✓
×
×
×
×
✓
✓
✓
Pou5f3.1
Pou5f3.2
Pou5f3.3
✓
✓
2922
POU2
POU2
POUV
Pou91, Oct91
Pou25, Oct25
Pou60, Oct60
Pou2
Pou2, Spg, Oct4,
Pou5f1
Acknowledgements
We thank Ira Blitz (UC Irvine) for critical discussions.
Competing interests
The authors declare no competing financial interests.
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Fig. 1. Model for the evolution of POUV genes in vertebrates. Dashed lines
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The use of divergent model organisms is a powerful approach for
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