Peijing Jeremy Wang

Animal chemosensory systems discriminate between complex mixtures of chemical compounds by leveraging large repertoires of chemoreceptor proteins. To organize information from many receptors, these systems often employ a one-receptor-type per cell organization (Fulton et al. 2024). This structure requires a gene regulatory mechanism that can coordinate the generation of many distinct types of sensory neurons, each expressing a different receptor (Yusuf and Monahan 2024; Danoff et al. 2025; Pourmorady and Lomvardas 2022; Bashkirova and Lomvardas 2019; Monahan and Lomvardas 2015; Brann and Datta 2020). Here we show that testis-expressed gene 15 ( Tex15 ) is a critical component in an epigenetic mechanism that safeguards diverse olfactory receptor (OR) choice in the mouse olfactory system. Tex15 is required to inhibit an initial wave of olfactory receptor gene transcription that occurs as olfactory sensory neuron progenitors differentiate. In Tex15 knockout ( Tex15-/- ) mice, this repression fails: the early-transcribed OR genes get expressed at abnormally high levels, get chosen at high rates, and come to dominate the neuronal population. This results in a profound reduction in the diversity of OR gene choice and disrupted spatial patterning of the olfactory epithelium, while maintaining the expression of one receptor per cell. These changes in OR gene expression are accompanied by reduced deposition of H3K9me3 heterochromatin on OR genes and the preferential formation of interchromosomal enhancer hubs around the dominant ORs. We propose that Tex15 directs a heterochromatin-based transcriptional repression mechanism that counter-balances early OR transcription, thereby preventing the heterogeneous onset of OR transcription from skewing OR choice.

The synaptonemal complex is a highly ordered proteinaceous structure that assembles between homologous chromosomes during the prophase I of meiosis. Conserved as a tripartite architecture across species, the synaptonemal complex plays a central role in chromosome synapsis, meiotic recombination, and faithful chromosome segregation. This review marks the 70th anniversary of the discovery of the synaptonemal complex by Montrose Moses in 1956. In mammals, the synaptonemal complex is composed of eight core (canonical) structural proteins: SYCP1, SYCP2, SYCP3, SYCE1, SYCE2, SYCE3, SIX6OS1, and TEX12. The archetypal synaptonemal complex consists of two lateral elements (SYCP2 and SYCP3), a central element (SYCE1/2/3, SIX6OS1, and TEX12), and numerous transverse filaments (SYCP1). A shared structural feature of synaptonemal complex components is the presence of coiled-coil domains. Although the tripartite organization of the synaptonemal complex is evolutionarily conserved, its constituent proteins exhibit little to no sequence homology across species. In addition to these core components, a number of proteins, including HORMAD1, HORMAD2, TRIP13, SKP1, CDCA5 (Sororin), UBE2I (UBC9), SYCP2L, HSPA2, PSMA8, and FKBP6, associate with the synaptonemal complex. Beyond serving as a structural scaffold essential for homolog synapsis, synaptonemal complex proteins interact with key recombination factors such as DMC1, RAD51, and TEX11, thereby regulating recombination progression and crossover formation. Genetic, biochemical, and structural analyses of synaptonemal complex components have provided important mechanistic insights into synaptonemal complex assembly and function, as well as their clinical relevance to non-obstructive azoospermia and premature ovarian insufficiency in humans.

Retrotransposon silencing and meiotic sex chromosome inactivation (MSCI) are critical for male germ cell development. MORC2, a DNA-binding ATPase, represses retrotransposons in mammalian somatic cells through association with the HUSH complex. However, the in vivo roles for MORC2 in germ cells remain unknown, as its loss leads to embryonic lethality. Here, we report two distinct functions of MORC2 during spermatogenesis. Embryonic germ cell-specific inactivation of MORC2 results in a failure in silencing of LINE1 and IAP retrotransposons in male germ cells, meiotic arrest, and male sterility. LINE1 and IAP elements are hypomethylated in MORC2-deficient testes, providing a molecular explanation for their activation. In contrast, postnatal loss of MORC2 prior to meiosis causes a failure in MSCI. Mechanistically, MORC2 binds to gene promoters and represses transcription of both autosomal and sex chromosome-linked genes through H3K9me3 deposition in meiotic cells with a preferential effect on sex chromosome-linked genes. Biochemically, MORC2 interacts with MORC1 and SETDB1 in testis. Our results demonstrate that MORC2 plays stage-dependent dual functions in male germ cells: retrotransposon silencing in pre-meiotic cells and MSCI in meiotic cells, through association with MORC1 and SETDB1, respectively.

P Jeremy Wang; The RNA-binding protein road map of spermatogenesis, Biology of Reproduction, , ioae138, https://doi.org/10.1093/biolre/ioae138

Meiotic progression requires coordinated assembly and disassembly of protein complexes involved in chromosome synapsis and meiotic recombination. Mouse TRIP13 and its ortholog Pch2 are instrumental in remodeling HORMA domain proteins. HORMAD proteins are associated with unsynapsed chromosome axes but depleted from the synaptonemal complex (SC) of synapsed homologs. Here we report that TRIP13 localizes to the synapsed SC in early pachytene spermatocytes and to telomeres throughout meiotic prophase I. Loss of TRIP13 leads to meiotic arrest and thus sterility in both sexes. Trip13-null meiocytes exhibit abnormal persistence of HORMAD1 and HOMRAD2 on synapsed SC and chromosome asynapsis that preferentially affects XY and centromeric ends. These major phenotypes are consistent with reported phenotypes of Trip13 hypomorph alleles. Trip13 heterozygous mice exhibit meiotic defects that are less severe than the Trip13-null mice, showing that TRIP13 is a dosage-sensitive regulator of meiosis. Localization of TRIP13 to the synapsed SC is independent of SC axial element proteins such as REC8 and SYCP2/SYCP3. Terminal FLAG-tagged TRIP13 proteins are functional and recapitulate the localization of native TRIP13 to SC and telomeres. Therefore, the evolutionarily conserved localization of TRIP13/Pch2 to the synapsed chromosomes provides an explanation for dissociation of HORMA domain proteins upon synapsis in diverse organisms.

During meiosis, homologous chromosomes undergo synapsis and recombination. HORMA domain proteins regulate key processes in meiosis. Mammalian HORMAD1 and HORMAD2 localize to unsynapsed chromosome axes but are removed upon synapsis by the TRIP13 AAA⁺ ATPase. TRIP13 engages the N-terminal region of HORMA domain proteins to induce an open conformation, resulting in disassembly of protein complexes. Here we report introduction of a 3×FLAG-HA tag to the N-terminus of HORMAD2 in mice. Co-immunoprecipitation coupled with mass spectrometry identified HORMAD1 and SYCP2 as HORMAD2-associated proteins in testis. Unexpectedly, the N-terminal tagging of HORMAD2 resulted in its abnormal persistence along synapsed regions in pachynema and ectopic localization to telomeres in diplonema. Super-resolution microscopy revealed that 3×FLAG-HA-HORMAD2 was distributed along the central region of the synaptonemal complex, whereas wild type HORMAD1 persisted along the lateral elements in 3×FLAG-HA-HORMAD2 meiocytes. Although homozygous mice completed meiosis and were fertile, homozygous males exhibited a significant reduction in sperm count. Collectively, these results suggest that the N-terminus of HORMAD2 is important for its timely removal from meiotic chromosome axes.

Meiotic progression requires coordinated assembly and disassembly of protein complexes involved in chromosome synapsis and meiotic recombination. The AAA+ ATPase TRIP13 and its orthologue Pch2 are instrumental in remodeling HORMA domain proteins. Meiosis-specific HORMAD proteins are associated with unsynapsed chromosome axes but depleted from the synaptonemal complex (SC) of synapsed chromosome homologues. Here we report that TRIP13 localizes to the synapsed SC in early pachytene spermatocytes and to telomeres throughout meiotic prophase I. Loss of TRIP13 leads to meiotic arrest and thus sterility in both sexes. Trip13-null meiocytes exhibit abnormal persistence of HORMAD1 and HOMRAD2 on synapsed SC and chromosome asynapsis that preferentially affects XY and centromeric ends. These findings confirm the previously reported phenotypes of the Trip13 hypomorph alleles. Trip13 heterozygous (Trip13+/-) mice also exhibit meiotic defects that are less severe than the Trip13-null mice, showing that TRIP13 is a dosage-sensitive regulator of meiosis. Localization of TRIP13 to the synapsed SC is independent of SC axial element proteins such as REC8 and SYCP2/SYCP3. The N- or C-terminal FLAG-tagged TRIP13 proteins are functional and recapitulate the localization of native TRIP13 to SC and telomeres in knockin mice. Therefore, the evolutionarily conserved localization of TRIP13/Pch2 to the synapsed chromosomes provides an explanation for dissociation of HORMA domain proteins upon chromosome synapsis in diverse organisms.

Meiotic progression requires coordinated assembly and disassembly of protein complexes involved in chromosome synapsis and meiotic recombination. The AAA+ ATPase TRIP13 and its orthologue Pch2 are instrumental in remodeling HORMA domain proteins. Meiosis-specific HORMAD proteins are associated with unsynapsed chromosome axes but depleted from the synaptonemal complex (SC) of synapsed chromosome homologues. Here we report that TRIP13 localizes to the synapsed SC in early pachytene spermatocytes and to telomeres throughout meiotic prophase I. Loss of TRIP13 leads to meiotic arrest and thus sterility in both sexes. Trip13 -null meiocytes exhibit abnormal persistence of HORMAD1 and HOMRAD2 on synapsed SC and chromosome asynapsis that preferentially affects XY and centromeric ends. These findings confirm the previously reported phenotypes of the Trip13 hypomorph alleles. Trip13 heterozygous ( Trip13 ^+/- ) mice also exhibit meiotic defects that are less severe than the Trip13 -null mice, showing that TRIP13 is a dosage-sensitive regulator of meiosis. Localization of TRIP13 to the synapsed SC is independent of SC axial element proteins such as REC8 and SYCP2/SYCP3. The N- or C-terminal FLAG-tagged TRIP13 proteins are functional and recapitulate the localization of native TRIP13 to SC and telomeres in knockin mice. Therefore, the evolutionarily conserved localization of TRIP13/Pch2 to the synapsed chromosomes provides an explanation for dissociation of HORMA domain proteins upon chromosome synapsis in diverse organisms.