Bedford, Lynn; (2002) Key functions for Id4 in gliogenesis and Id2 in spermatogenesis discovered by the analysis of knockout mice. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Id proteins belong to the family of helix-loop-helix (HLH) transcription factors, and are well known as positive regulators of cell growth and negative regulators of cell differentiation. The mammalian Id subfamily currently has four members, Id1-Id4, and the Id proteins are key intracellular factors in numerous developmental processes. The results presented here demonstrate novel functions for Id4 and Id2 in nervous system and germ cell development respectively. Here we describe the generation of Id4 knockout mice, and present evidence that Id4 is necessary for normal development of mice. Id4 knockout mice exhibited reduced viability, and mice surviving to adulthood had drastically altered brain morphology, with an overall reduction in size, indicating fewer neuronal and glial cells, but larger ventricles. Analysis of neural-specific markers revealed a disproportional reduction in the number of glia, but not neurons, in the adult Id4-/- brain. In vitro, we show that adult neural stem cells (NSCs) lacking Id4 have a significantly reduced proliferation capacity and prematurely differentiate into glia. Neuronal differentiation in vitro was independent of Id4. Together, the results indicate that Id4 is a crucial intracellular factor that functions to positively regulate NSC proliferation and negatively regulate glial cell differentiation. We also show that male Id2 knockout mice (Yokota et al., 1999) have reduced fertility, which correlates with defective spermatogenesis. Although testis weight of homozygous Id2 mutant mice was not significantly affected, approximately 60% of the Id2-/- seminiferous tubules were undergoing defective spermatogenesis. We present data that suggests Id2 is not involved in Sertoli cell proliferation, but suggest that Id2 is involved in regulating Sertoli cell differentiated functions. Id2 may also function in meiotic and post-meiotic germ cells. Together, the results show that the presence of a functional Id2 protein in the testis, be it in the Sertoli cell and/or germ cell development, is crucial for normal spermatogenesis.

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