Germline Stem Cell Maintenance during Mammalian Spermatogenesis

2006 new Scholar Award in aging

Proper organ development and maintenance is often accomplished through multiple cell types within a tissue that express distinct gene products and collectively support common functions. For example, the mammalian testis is composed of male germ cells (the gametes) and supporting somatic cells that together promote a highly regulated series of developmental transitions in the seminiferous tubules of the testis to produce functional spermatozoa. Spermatogenesis is initiated by the commitment of true spermatogonial stem cells (SSCs) that can self-renew and differentiate, to continuously replenish new waves of differentiating germ cells throughout adulthood in normal males. These SSCs exist within an unexplored stem cell niche in the mammalian testis that may be the key to understanding normal testicular aging in humans and the premature cessation of spermatogenesis associated with male infertility.

Work in our laboratory is focused on identifying and characterizing key regulators of gene expression which are critical for the normal maintenance of the SSC niche in mammals. To this end, we have established and begun to characterize a mutant mouse model in which we targeted disruption of a transcriptional regulatory protein called TAF4b. Male TAF4b-deficient mice are viable and are able to initiate spermatogenic differentiation, but are only temporarily fertile. These mutant mice undergo premature testicular atrophy and are thus unable to maintain spermatogenesis into adulthood. Since TAF4b is a subunit of the multi-protein core transcription factor TFIID, we hypothesize that TAF4b is required for the selective expression of gene products necessary for normal testis homeostasis and function. Thus, we propose to characterize the cell types, biological processes and molecular targets associated with TAF4b function in the mouse testis. In this regard, understanding the mechanism of TAF4b-dependent testis-specific gene expression patterns required for the maintenance of the SSC niche and spermatogenesis in the adult mouse testis may reveal key regulatory mechanisms in place that prevent premature testicular aging in humans.

Elucidating a new paradigm of male reproductive aging may also be relevant to the study of aging in other organ systems of the body that utilize stem cell renewal, such as the immune system and the skin. Each stem cell renewal system can have its own unique features but also may share the function of common factors and mechanisms. Given the potential medical uses for stem cell therapies in the context of the clinical management of somatic aging phenotypes, such as neurodegeneration and cardiovascular disease, deciphering the basic mechanisms underlying germline stem cell renewal in the testis may prove relevant to the general understanding of stem cell biology and its implications for aging-related diseases in humans.