Developmental Cell
Previews
which extent pH-dependent lipid proton-
ation affects lipid signaling, and whether
similar mechanisms also operate in other
organisms.
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MEIOSIN: A New Watchman of Meiotic
Initiation in Mammalian Germ Cells
Jon M. Oatley1,* and Michael D. Griswold1
1Center for Reproductive Biology, School of Molecular Biosciences, College of Veterinary Medicine, Washington State University, Pullman,
WA 99164, USA
*Correspondence: joatley@wsu.edu
https://doi.org/10.1016/j.devcel.2020.02.002
The capacity to undergo meiosis defines vertebrate germ cells, yet mechanisms driving initiation of this
specialized process are largely undefined. In this issue of Developmental Cell, Ishiguro et al. (2020) identified
the transcription factor MEIOSIN as a gatekeeper of meiotic initiation in both male and female germ cells.
Gametogenesis is the process by which
sperm and eggs are generated to serve
as conduits for transmission of genetic in-
formation to subsequent generations. To
achieve this in mammalian species,
diploid undifferentiated germ cells in the
form of oogonia in the ovaries of XX indi-
viduals or spermatogonia in the testes of
XY individuals transition from undergoing
mitotic divisions to meiotic divisions that
will produce haploid genomes. Many pre-
vious studies have shed light on retinoic
acid (RA) as a triggering signal for this
mitotic-to-meiotic transition which occurs
in the ovary during fetal development but
post-pubertally in the testis (Bowles
et al., 2006). A direct target gene of RA
signaling in both oogonia and spermato-
gonia of several species is Stra8 and in
mice genetic inactivation results in
impaired meiotic initiation (Anderson
et al., 2008). These findings have formed
the basis of a model in which STRA8
Lemmon, M.A. (2008). Membrane recognition by
phospholipid-binding domains. Nat. Rev. Mol.
Cell Biol. 9, 99–111.
Loewen, C.J.R., Gaspar, M.L., Jesch, S.A., Delon,
C., Ktistakis, N.T., Henry, S.A., and Levine, T.P.
(2004). Phospholipid metabolism regulated by a
transcription factor sensing phosphatidic acid.
Science 304, 1644–1647.
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Lacas-Gervais, S., Drin, G., and Antonny, B.
(2013). A four-step cycle driven by PI(4)P hydroly-
sis directs sterol/PI(4)P exchange by the ER-
Golgi tether OSBP. Cell 155, 830–843.
Orij, R., Brul, S., and Smits, G.J. (2011).
Intracellular pH is a tightly controlled signal in
yeast. Biochim. Biophys. Acta 1810, 933–944.
acts as an inducer of the mitotic-to-
meiotic transition during mammalian
gametogenesis.
Although a role for STRA8 in gameto-
genesis has been revealed by previous
studies, the mechanism of action has re-
mained largely undefined. In this issue of
Development Cell, Ishiguro et al. (2020),
have identified a binding partner of
STRA8 in the germline of both male and
female mice that is also regulated by RA
signaling and plays a critical role in
meiotic initiation. The authors genetically
engineered a mouse line to contain an
epitope-tagged Stra8 allele and used tan-
dem immunoprecipitation followed by
proteomic analyses to define the binding
protein repertoire of tagged STRA8 pro-
tein in differentiating germ cells. One of
the identified binding proteins was found
to be encoded by a hypothetical gene
(GM4969) in the mouse genome, which
was named MEIOSIN by the authors.
Developmental Cell 52, February 24, 2020 ª 2020 Elsevier Inc. 397
Schink, K.O., Tan, K.-W., and Stenmark, H. (2016).
Phosphoinositides in Control of Membrane
Dynamics. Annu. Rev. Cell Dev. Biol. 32, 143–171.
Shin, J.J.H., Liu, P., Chan, L.J., Ullah, A., Pan, J.,
Borchers, C.H., Burke, J.E., Stefan, C., Smits,
G.J., and Loewen, C.J.R. (2020). pH Biosensing
by PI4P Regulates Cargo Sorting at the TGN.
Dev. Cell 52, this issue, 461–476.
Umebayashi, K., and Nakano, A. (2003). Ergosterol
is required for targeting of tryptophan permease to
the yeast plasma membrane. J. Cell Biol. 161,
1117–1131.
Young, B.P., Shin, J.J.H., Orij, R., Chao, J.T., Li,
S.C., Guan, X.L., Khong, A., Jan, E., Wenk, M.R.,
Prinz, W.A., et al. (2010). Phosphatidic acid is a
pH biosensor that links membrane biogenesis to
metabolism. Science 329, 1085–1088.
Motif predictions of the amino acid
sequence indicated that MEIOSIN con-
tains helix-loop-helix (HLH) and high-
mobility-group (HMG) domains, thus clas-
sifying it as a transcription factor. Further
characterization studies revealed that
MEIOSIN was expressed specifically in
germ cells at the initiation of meiotic pro-
phase in males and females. In addition,
knockout of MEIOSIN resulted in impaired
development of meiocytes (oocytes in fe-
males and spermatocytes in males), lead-
ing to infertility.
During ovarian development in mice,
RA signaling around embryonic day 13.5
induces STRA8 expression in oogonia
and the initiation of meiotic prophase to
generate oocytes (Baltus et al., 2006).
Similarly, MEIOSIN was found to also be
expressed in oocytes during the timing
of normal meiotic initiation and persisted
into the oocyte phase. In the ovaries of
Meiosin knockout mice, STRA8 was still

expressed by germ cells at embryonic
day 13.5, but proper pairing of homolo-
gous chromosomes to create sites of
crossover failed to occur, thus demon-
strating a block in the initiation of meiotic
prophase. At the adult stage of develop-
ment, ovaries of Meiosin knockout mice
underwent major degeneration with little
to no follicle development. However,
some oocyte-like cells encapsulated as
follicles were still observed, but the chro-
mosomal complement of these cells was
reminiscent of mitotic rather than meiotic
DNA replication, indicating that MEIOSIN
has an important role in the regulation of
the mitosis-to-meiosis switch in female
germ cells. Interestingly, oocyte-like cells
that seemingly skip a meiotic cell division
also arise in ovaries of mice that are defi-
cient for STRA8, further corroborating a
functional collaboration with MEIOSIN in
the mitosis-to-meiosis switch of XX
germ cells.
During spermatogenesis, meiotic cells
are produced postnatally from the transi-
tion of differentiating spermatogonia to
preleptotene spermatocytes in response
to RA signaling. A pulse of RA from the
Sertoli cells in the first wave or from the
Sertoli cells and germ cells in the subse-
quent waves drives this transition that is
marked by the induction of Stra8 in sper-
matogonia and in preleptotene spermato-
cytes (Tong et al., 2013). The first-time
male germ cells become responsive to
RA signaling is in the transition from an
undifferentiated-to-differentiating sper-
matogonial state. During this process,
STRA8 expression, along with other hall-
mark transcriptome responses to RA
signaling and some genes unique to
meiosis, is induced but the cells do not
initiate meiotic prophase; rather, mitosis
resumes to amplify the population
numbers (Chen et al., 2018).
In mice, the differentiating spermato-
gonia that form after initial RA signaling
undergo six additional mitotic divisions,
and at the second induction of RA
signaling with the appearance of prelep-
totene spermatocytes, the mitosis-to-
meiosis switch is induced. Interestingly,
in a recent study it was shown that in
mouse testes lacking the ability to make
RA in either germ cells or Sertoli cells,
spermatogonia at postnatal day 3 can
enter the differentiation pathway when
mice are given a single injection of
RA (Teletin et al., 2019). However, the
398 Developmental Cell 52, February 24, 2020
spermatocytes originating from those
spermatogonia initiate meiosis and ex-
press meiotic markers, including STRA8,
despite the lack of internally derived sour-
ces of RA in the seminiferous epithelium.
Surprisingly, the results of Ishiguro et al.
show that Meiosin is a direct target gene
of RA receptor signlaing but, unlike
Stra8, is not activated by initial RA expo-
sure that drives the undifferentiated-to-
differentiating spermatogonial transition;
however, expression is induced by the
second exposure to RA. These observa-
tions beg the question of why Meiosin
expression is not activated in spermato-
gonia upon initial exposure to RA. A partial
answer to this was uncovered by Ishiguro
et al. which found expression of the tran-
scriptional repressor DMRT1, a known
suppressor of meiotic initiation, to be mu-
tally exclusive of MEIOSIN expression in
male germ cells. Moreover, by reanalyz-
ing previously reported DMRT1 ChIP-
seq data (Murphy et al., 2015), they
discovered binding to the 50 upstream re-
gion of the Meiosin locus. Together, these
findings indicate that STRA8 in itself is not
able to initiate meiotic prophase in sper-
matogonia but requires key binding part-
ners such as MEIOSIN, and the ability
for their encoding genes to be expressed
is unmasked during spermatogonial dif-
ferentiation through downregulation of
suppressors such as DMRT1.
The expression of MEIOSIN was shown
to be restricted to preleptotene spermato-
cytes in testes of mice throughout adult-
hood, but it could be suppressed following
consecutive treatments with the com-
pound WIN 18,446 to ablate normal testic-
ular RA synthesis. In addition, systemic in-
jection of RA into mice after WIN 18,446
suppression resulted in upregulation of
MEIOSIN, suggesting that, similar to
STRA8, MEIOSIN is a direct target of RA
signaling in male germ cells. In testes of
Meiosin knockout mice, post-meiotic
germ cells do not form and spermatogen-
esis is halted at what seems to be a
quasi-preleptotene stage, indicating a
defect in meiotic entry rather than pro-
phase progression. Thus, similar to the sit-
uation in the female germline, MEIOSIN in
the male seems to play a key role in regu-
lating the switch from mitosis to meiosis.
Lastly, an important observation of the
Ishiguro et al. (2020) study is that, upon
querying the ENSEMBL TBLASTN data-
base for molecules with the first 20 amino
Developmental Cell
Previews
acid residues of mouse MEIOSIN, pro-
teins with high similarity of the two func-
tional domains (HLH and HMG) in humans
and rats, as well as a reptilian and fish
species, were identified. In addition, the
genomic loci for nucleotide sequence
that encodes for the putative MEIOSIN
proteins in these other species was found
to have partial synteny to the gene
sequence in the mouse genome. While
these findings suggest an ancient origin
of the Meiosin gene as a conserved gate-
keeper of meiosis in vertebrates, deter-
mining whether expression in other spe-
cies is regulated in a manner similar to
mice to ensure proper timing for exerting
an influence on meiotic prophase will be
an important question to address in future
studies.
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