Enhanced Genetic Integrity in Mouse Germ Cells1

Abstract

Genetically based diseases constitute a major human health burden, and de novo germline mutations represent a source of heritable genetic alterations that can cause such disorders in offspring. The availability of transgenic rodent systems with recoverable, mutation reporter genes has been used to assess the occurrence of spontaneous point mutations in germline cells. Previous studies using the lacI mutation reporter transgenic mouse system showed that the frequency of spontaneous mutations is significantly lower in advanced male germ cells than in somatic cell types from the same individuals. Here we used this same mutation reporter transgene system to show that female germ cells also display a mutation frequency that is lower than that in corresponding somatic cells and similar to that seen in male germ cells, indicating this is a common feature of germ cells in both sexes. In addition, we showed that statistically significant differences in mutation frequencies are evident between germ cells and somatic cells in both sexes as early as mid-fetal stages in the mouse. Finally, a comparison of the mutation frequency in a general population of early type A spermatogonia with that in a population enriched for Thy-1-positive spermatogonia suggests there is heterogeneity among the early spermatogonial population such that a subset of these cells are predestined to form true spermatogonial stem cells. Taken together, these results support the disposable soma theory, which posits that genetic integrity is normally maintained more stringently in the germ line than in the soma and suggests that this is achieved by minimizing the initial occurrence of mutations in early germline cells and their subsequent gametogenic progeny relative to that in somatic cells.

The Homeobox Transcription Factor RHOX10 Drives Mouse Spermatogonial Stem Cell Establishment

“…In support, two morphologically distinct ProSG generated at birth have been identified that exhibit morphological similarities with undifferentiated spermatogonia and differentiating A-spermatogonia, respectively (Kluin and de Rooij, 1981). Furthermore, a recent study showed that germ cell subsets differ considerably in their mutation frequencies in a manner consistent with the notion that a subset of ProSG with enhanced genome fidelity (low mutation rate) are predestined to become SSCs (Murphey et al, 2013). Our results also support the existence of ProSG heterogeneity.…”

“…The model posits that Rhox10 drives both the T1-ProSG-to-T2-ProSG differentiation step and the ProSG migration step, which temporal studies suggest may occur simultaneously. Depicted are two kinds of T2-ProSG, each with a different fate, a possibility that is consistent with published studies (Kluin and de Rooij, 1981; Murphey et al, 2013), but has not been directly demonstrated. SC, Sertoli cell.…”

Toward a More Precise and Informative Nomenclature Describing Fetal and Neonatal Male Germ Cells in Rodents1

“…In addition, Yoshida et al [58][59][60][61], Shinohara et al [62,63], and others [65] have reported results that raise the possibility that distinct subpopulations of early type A spermatogonia can be distinguished on the basis of marker gene expression, and that these different subpopulations may show differences in their potential to become functional SSCs. Finally, a recent analysis of the frequencies of spontaneous mutations detectable at different stages of prespermatogenesis and spermatogenesis also indicated the existence of distinct subpopulations of T 1 -and T 2 -prospermatogonia and early spermatogonia that differ with respect to the potential to form functional SSCs [66].…”

“…Whether or not mitotic quiescence is required to facilitate this epigenetic reprogramming is not known, but the correlation between these two events is intriguing. Finally, during the phase of renewed mitotic activity of male germ cells just prior to the spermatogonial stage, there is further expansion of the male germ cell pool, and there is also evidence that differences in developmental potential among subsequent spermatogonia are first manifest at this time [58][59][60][61][62][63][64][65][66]. These distinctions in cellular activity among male germ cells at various stages of fetal and neonatal development warrant distinguishing terms to identify each different male germ cell function or activity during this period.…”

Environmental challenges may impact on somatic repair

“…It is known for example, that DNA repair systems including GG-NER (Global Genome Nucleotide Excision Repair) are specifically active in germ line cells and contribute towards the effective repair of the germ DNA, but these are also active in somatic cells [12] 2. Efficient selection of fully functional germ cells which are allowed to propagate at the expense of less efficient germ cells [13]. A relevant concept here is that of apoptosis regulation, which may also depend on neuronal inputs as will be discussed below 3.…”