Stem cell regulatory mechanisms are difficult to study because self-renewal and production of differentiated progeny, which are both strictly controlled, occur simultaneously in these cells. To focus on the self-renewal mechanism alone, we investigated the behavior of germinal stem cells (GSCs) in progeny-deficient testes with defective GSC differentiation. In these testes, we found that the proliferation of undifferentiated spermatogonia, some of which are GSCs, was accelerated by high concentrations of glial cell line-derived neurotrophic factor (GDNF). Furthermore, we found that follicle-stimulating hormone (FSH) stimulation via homeostatic control was one of the major regulators of GDNF concentration. These results suggest that in mammalian testes, GSC proliferation and population size are regulated homeostatically by the GDNF/FSH pathway.
Transcription factor GATA-1 is required for the terminal differentiation of both the primitive and definitive erythroid cell lineages, and yet the regulatory mechanisms of GATA-1 itself are not well understood. To clarify how the GATA-1 gene is transcriptionally controlled in vivo, presumptive regulatory regions of the gene were tested by fusion to a reporter gene and then examined in transgenic mice. We found that a transcriptional control element located between ؊3.9 and ؊2.6 kb 5 to the erythroid first exon serves as an activating element and that this sequence alone is sufficient to recapitulate the expression of GATA-1 (but uniquely in primitive erythroid cells). Addition of sequences from the GATA-1 first intron to this upstream element provides a necessary and sufficient condition for complete recapitulation of GATA-1 expression in both primitive and definitive erythroid cells. The first intron element does not possess intrinsic transcriptional activation potential when linked to the GATA-1 gene promoter but rather requires the upstream activating element for its activity. These experiments show that GATA-1 gene expression is regulated by discrete transcriptional control elements during definitive and primitive erythropoiesis: The 5 element displays properties anticipated for a primitive erythroid cell-specific activating element, and the novel element within the GATA-1 first intron specifically augments this activity in definitive erythroid cells.
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