hnRNPH1 recruits PTBP2 and SRSF3 to modulate alternative splicing in germ cells

Abstract

Coordinated regulation of alternative pre-mRNA splicing is essential for germ cell development. However, the underlying molecular mechanism that controls alternative mRNA expression during germ cell development remains elusive. Herein, we show that hnRNPH1 is highly expressed in the reproductive system and recruits the PTBP2 and SRSF3 to modulate the alternative splicing in germ cells. Conditional knockout Hnrnph1 in spermatogenic cells causes many abnormal splicing events, thus affecting the genes related to meiosis and communication between germ cells and Sertoli cells. This is characterized by asynapsis of chromosomes and impairment of germ-Sertoli communications, which ultimately leads to male sterility. Markedly, Hnrnph1 germline-specific mutant female mice are also infertile, and Hnrnph1-deficient oocytes exhibit a similar defective synapsis and cell-cell junction as seen in Hnrnph1-deficient male germ cells. Collectively, our data support a molecular model wherein hnRNPH1 governs a network of alternative splicing events in germ cells via recruitment of PTBP2 and SRSF3.

Chromodomain helicase DNA-binding domain 2 maintains spermatogonial self-renewal by promoting chromatin accessibility and mRNA stability

“…Further immunofluorescence staining of SYCP1 and SYCP3 in testicular cell smears showed more abnormal chromosomal synapsis in pachytene spermatocytes of Chd2 +/− mice, including the mislocalization of SYCP1 to unsynapsed sex chromosomes and loss of SYCP3 on autosomal and separated X-Y chromosomes ( Figures 3 C and 3D). 38 Such defective synapses may affect homologous recombination in spermatogenesis. Interestingly, Chd1 , a member of the Chd1 - Chd2 subfamily, has been found to reduce histone occupancy near the DSB ends and promotes DSB repair by homologous recombination.…”

The HNRNPF/H RNA binding proteins and disease

“…However, the tissue-specific depletion of HNRNPF (principally in kidney tubules) achieved using a Pax8-Cre-derived mouse line did result in viable mice which exhibited hypertension and glycosuria (Lo et al, 2019). Notably, germline Hnrnph1-deleted mice and the Pax8-Cre-HNRNPF knockout mice exhibited evidence of altered maturation of specific transcripts, consistent with their functions as alternative splicing factors (Feng et al, 2022;Lo et al, 2019).…”

Transcriptome sequencing reveals the effects of circRNA on testicular development and spermatogenesis in Qianbei Ma goats

“…For example, circRNA_12624 in 0Y vs. 6Y, 0Y vs. 12Y and 0Y vs. 18Y was derived from the ATG5 gene. ATG5 is a cytoplasmic protein mainly expressed in the nucleus, which can be used as a key factor to induce autophagy, regulate cell growth cycle and spermatogenesis of male animals ( 37 – 39 ).The 10 DEcircRNAs in 6Y vs. 12Y, 6Y vs. 18Y and 12Y vs. 18Y were derived from four genes encoding genes associated with germ cell development and spermatogenesis [ PTBP2 ( 40 ), PRMT5 ( 41 ), PLK4 , SYCE1 ( 42 )]. Of these, circRNA_04355 , circRNA_04356 and circRNA_04357 were all derived from the PLK4 gene, which has been shown to play a role in the initiation of spermatogenesis ( 43 ).…”