PUMILIO-mediated translational control of somatic cell cycle program promotes folliculogenesis and contributes to ovarian cancer progression.

Translational control is a fundamental mechanism regulating animal germ cell development. Gonadal somatic cells provide support and microenvironment for germ cell development to ensure fertility, yet the roles of translational control in gonadal somatic compartment remain largely undefined. We found that mouse homolog of conserved fly germline stem cell factor Pumilio, PUM1, is absent in oocytes of all growing follicles after the primordial follicle stage, instead, it is highly expressed in somatic compartments of ovaries. Global loss of Pum1, not oocyte-specific loss of Pum1, led to a significant reduction in follicular number and size as well as fertility. Whole-genome identification of PUM1 targets in ovarian somatic cells revealed an enrichment of cell proliferation pathway, including 48 key regulators of cell phase transition. Consistently granulosa cells proliferation is reduced and the protein expression of the PUM-bound Cell Cycle Regulators (PCCR) were altered accordingly in mutant ovaries, and specifically in granulosa cells. Increase in negative regulator expression and decrease in positive regulators in the mutant ovaries support a coordinated translational control of somatic cell cycle program via PUM proteins. Furthermore, postnatal knockdown, but not postnatal oocyte-specific loss, of Pum1 in Pum2 knockout mice reduced follicular growth and led to similar expression alteration of PCCR genes, supporting a critical role of PUM-mediated translational control in ovarian somatic cells for mammalian female fertility. Finally, expression of human PUM protein and its regulated cell cycle targets exhibited significant correlation with ovarian cancer and prognosis for cancer survival. Hence, PUMILIO-mediated cell cycle regulation represents an important mechanism in mammalian female reproduction and human cancer biology.

Human skin dermis-derived fibroblasts are a kind of functional mesenchymal stromal cells: judgements from surface markers, biological characteristics, to therapeutic efficacy.

BACKGROUND: Human mesenchymal stromal cells (MSCs) have been widely advocated to clinical use. Human skin dermis-derived fibroblasts shared similar cellular morphology and biological characteristics to MSCs, while it still keeps elusive whether fibroblasts are functionally equivalent to MSCs for therapeutic use. METHODS: We isolated various fibroblasts derived from human foreskins (HFFs) and human double-fold eyelids (HDF) and MSCs derived from human umbilical cords (UC-MSCs), and then comprehensively investigated their similarities and differences in morphology, surface markers, immunoregulation, multilineage differentiation, transcriptome sequencing, and metabolomics, and therapeutic efficacies in treating 2,4,6-Trinitrobenzenesulfonic acid (TNBS) induced colitis and carbontetrachloride (CCL4) induced liver fibrosis. RESULTS: Fibroblasts and UC-MSCs shared similar surface markers, strong multilineage differentiation capacity, ability of inhibiting Th1/Th17 differentiation and promoting Treg differentiation in vitro, great similarities in mRNA expression profile and metabolites, and nearly equivalent therapeutic efficacy on TNBS-induced colitis and CCL4-induced hepatic fibrosis. CONCLUSION: Human skin dermis-derived fibroblasts were a kind of functional MSCs with functionally equivalent therapeutic efficacy in treating specific complications, indicating fibroblasts potentially had the same lineage hierarchy of origin as MSCs and had a remarkable potential as an alternative to MSCs in the treatment of a variety of diseases.

RNA binding protein BOULE forms aggregates in mammalian testis.

Amyloids have traditionally been considered pathologic protein aggregates which contribute to neurodegeneration. New evidence however increasingly suggests that non-pathological amyloids are formed in animals during normal development. Amyloid-like aggregate formation was originally thought to be a conserved feature of animal gametogenesis. This hypothesis was based on findings which suggest that regulated amyloid formations govern yeast meiosis by way of meiosis-specific RNA binding proteins. Additional support came from studies which demonstrate that DAZL, a mammalian gametogenesis-specific RNA binding protein, also forms SDS-resistant aggregates in vivo. Here, we report evidence of aggregated BOULE formations, another DAZ family protein, during sperm development. Data suggest that in mouse testis, BOULE forms SDS-resistant amyloid-like aggregates. BOULE aggregate formation correlates with dynamic developmental expression during spermatogenesis but disappeared in Boule knockout testis. We also mapped essential small region in vitro BOULE aggregations, immediately downstream DAZ repeats, and found that aggregations positively correlated with temperature. We also performed enhanced UV cross-linking immunoprecipitation on BOULE aggregates from mouse testes and found that aggregates bind with a large number of spermatogenesis-related mRNAs. These findings provide insight into the amyloidogenic properties of gametogenesis-specific RNA binding proteins as a conserved feature in mammalian reproduction. Further investigation is warranted to understand the functional significance of BOULE amyloid-like formation during mouse spermatogenesis.