Abstract
Development of the ovary or testis is required to establish reproductive competence. Gonad development relies on key cell fate decisions that occur early in embryonic development and are actively maintained. During gonad development, both germ cells and somatic cells proliferate extensively, a process facilitated by cell cycle regulation. This review focuses on the Cip/Kip family of cyclin-dependent kinase inhibitors (CKIs) in mouse gonad development. We particularly highlight recent single-cell RNA sequencing studies that show the heterogeneity of cyclin-dependent kinase inhibitors. This diversity highlights new roles for cell cycle inhibitors in controlling and maintaining female fertility.
Highlights
INK4 and Cip/Kip are two main families of cyclindependent kinase inhibitors
Cip/Kip proteins are abundantly expressed in the early gonad, and importantly, deletion of the Cip/Kip family members in mice leads to unexpected gonad-specific fertility phenotypes in both sexes (Fero et al 1996; Holsberger et al 2005; Rajareddy et al 2007; Lin et al 2015)
More interrogation of the CHIP-seq data sets is needed to map this network of cell cycle control in the gonad. This indicates the male program represses cyclin dependent kinase inhibitor 1B (Cdkn1b) in the embryonic testis, but more importantly suggests that the key female factor forkhead box L2 (FOXL2) is capable of promoting Cdkn1b expression. This information, when combined with the RNA sequencing data sets (Stévant et al 2018, 2019), illustrates that expression of Cip/Kip family members in the supporting cell lineage contributes to the mechanisms of primary gonadal sex determination while they are in turn regulated by known players in this process
Summary
Around embryonic day (E) 9.5, where proliferating cells form a layer on the mesonephros (the embryonic kidney) (Hu et al 2013). This indicates the male program represses Cdkn1b in the embryonic testis, but more importantly suggests that the key female factor FOXL2 is capable of promoting Cdkn1b expression This information, when combined with the RNA sequencing data sets (Stévant et al 2018, 2019), illustrates that expression of Cip/Kip family members in the supporting cell lineage contributes to the mechanisms of primary gonadal sex determination while they are in turn regulated by known players in this process. The ovaries in these three global deletion models do not match the fast growth rate or the size of the male testis, and p21cip1-null mice and p57kip2-null female mice are fertile (Nakayama and Nakayama 1998) These data support the concepts of redundancy between multiple dormancy factors, and/or the presence of a gene regulatory network with cofactors that regulate each other. Conditional deletion of p27kip from the pregranulosa cell lineage would confirm whether an interaction exists between p27kip in the pregranulosa cells and the initiation of meiosis in the germ cells, linking pregranulosa cell signaling to cell cycle control in the female germ cells
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