Dennd1a, a susceptibility gene for polycystic ovary syndrome, is essential for mouse embryogenesis

Abstract

Background The DENND1A has been identified as a guanine nucleotide exchange factor for small GTPase Rab35, which functions in endocytic trafficking to mediate the recycling of selective cargos. Genetic alterations within the DENND1A gene have been implicated in human disease such as polycystic ovary syndrome (PCOS). However, the role of DENND1A in developmental and reproductive processes is largely unknown. Results Using Dennd1a gene knockout mice, we uncovered that homogeneous Dennd1a−/− mutants died around embryonic day (E) 14.5. The brain of Dennd1a−/− embryos exhibited defects, partially attributed to the dysregulation of cell division and survival in the telencephalon. The transcription of Fgf8 mRNA was ectopically elevated in the dorsal midline of telencephalon, concomitant with a decrease of active β‐catenin and Axin2 in the brain of Dennd1a−/− embryos. During liver morphogenesis, the ablation of Dennd1a impaired hepatic cell proliferation, the differentiation of hepatocyte, and hepatic hematopoiesis. In addition, loss of Dennd1a also affected the development of primordial germ cells. Conclusions We demonstrate that Dennd1a, a susceptibility gene for PCOS, is essential for embryogenesis, probably through the mediation of endocytic recycling of selective cargos that are involved in cell signaling crucial for the development of multiple embryonic organ systems.

Whole-genome sequencing of Chinese native goat offers biological insights into cashmere fiber formation

“…Furthermore, the expression of LHX2 was upregulated during hair follicle differentiation, and the expression abundance was constant throughout the development cycle in secondary hair follicles of cashmere goats (Wu et al 2020;Yang et al 2020). In contrast, DENND1A and CRB2, which function in endocytic trafficking to mediate the recycling of selective cargos and early embryonic development, respectively (Xiao et al 2011;Shi et al 2019), were expressed lowly in the fetal stage of goat skin and showed very low expression during the cycle of adult cashmere fiber growth (Fig. 6c).…”

Human DENND1A.V2 Drives Cyp17a1 Expression and Androgen Production in Mouse Ovaries and Adrenals

“…However, this assumes that the hDENND1A.V2 protein is not itself a factor preventing the creation of high expressing mice. Shi et al reported that knockout of the mouse Dennd1a gene results in embryonic lethality, revealing that the DENND1A protein is essential for embryonic development and viability [22]. It is possible that the human protein interferes with critical functions of the endogenous mouse DENND1A protein, selecting against transgenic mice producing high levels of hDENND1A.V2.…”

Initiation of oogenesis and meiosis in the fetal ovary depends on Dennd1a-mediated production of Wnt5a and retinoic acid from the somatic niches

“…Previous study revealed that Dennd1a is essential for mouse embryogenesis, and homozygous deletion of Dennd1a causes embryonic mouse lethality. Moreover, disruption of Dennd1a impairs the migration and differentiation of fetal germ cells [7]. In mouse, the population of primordial germ cells (PGCs) arise during gastrulation in the extra-embryonic mesoderm of the posterior amniotic fold, distinguished by high alkaline phosphatase (AP) activity [8].…”

“…PGCs at embryonic day 7.5 (E7.5) migrate from the base of allantois, then through the hindgut endoderm and mesentery before colonizing the genital ridge by E11.5 [9]. Dennd1a deficiency affects the migration of PGCs and results in a significant reduction in gonadal germ cell numbers [7].…”

“…In female mice, expression of spermatogenesis and oogenesis bHLH transcription factor 2 (Sohlh2) begins in the germLine as early as E12.5, which is an essential regulator of oocyte differentiation, independent of meiosis [11]. Since Sohlh2 mRNA expression is significantly low in the fetal ovary of Dennd1a-null embryo at E13.5, it suggests that Dennd1a may be involved in the regulation of Sohlh2 during fetal ovary development [7].…”