Abstract
Stem cells ensure tissue homeostasis through the production of differentiating and self-renewing progeny. In some tissues, this is achieved by the function of a definitive stem cell niche. However, the mechanisms that operate in mouse spermatogenesis are unknown because undifferentiated spermatogonia (Aundiff) are motile and intermingle with differentiating cells in an ‘open’ niche environment of seminiferous tubules. Aundiff include glial cell line-derived neurotrophic factor receptor α1 (GFRα1)+ and neurogenin 3 (NGN3)+ subpopulations, both of which retain the ability to self-renew. However, whereas GFRα1+ cells comprise the homeostatic stem cell pool, NGN3+ cells show a higher probability to differentiate into KIT+ spermatogonia by as yet unknown mechanisms. In the present study, by combining fate analysis of pulse-labeled cells and a model of vitamin A deficiency, we demonstrate that retinoic acid (RA), which may periodically increase in concentration in the tubules during the seminiferous epithelial cycle, induced only NGN3+ cells to differentiate. Comparison of gene expression revealed that retinoic acid receptor γ (Rarg) was predominantly expressed in NGN3+ cells, but not in GFRα1+ cells, whereas the expression levels of many other RA response-related genes were similar in the two populations. Ectopic expression of RARγ was sufficient to induce GFRα1+ cells to directly differentiate to KIT+ cells without transiting the NGN3+ state. Therefore, RARγ plays key roles in the differentiation competence of NGN3+ cells. We propose a novel mechanism of stem cell fate selection in an open niche environment whereby undifferentiated cells show heterogeneous competence to differentiate in response to ubiquitously distributed differentiation-inducing signals.
Highlights
The integrity of tissue homeostasis is maintained by the balanced self-renewal and differentiation of stem cells
We found that glial cell line-derived neurotrophic factor receptor α1 (GFRα1)+ and neurogenin 3 (NGN3)+ subpopulations of are unknown because undifferentiated spermatogonia (Aundiff) show a differential competence to differentiate in response to retinoic acid (RA), which is achieved by restricted RARγ expression in NGN3+ cells
To better understand stem cell function in tissues with an open niche environment, we investigated the mechanisms underlying the fate decision of Aundiff during mouse spermatogenesis
Summary
The integrity of tissue homeostasis is maintained by the balanced self-renewal and differentiation of stem cells. Stem cells cluster in an anatomically specialized (‘closed’ or ‘definitive’) niche that directs cell fate decisions. These include the testicular hub and ovariolar cap cells in Drosophila, gonadal distal tip cells of Caenorhabditis elegans and mammalian intestinal crypts. Stem cells appear to be distributed over an extended area, designated as an ‘open’ or ‘facultative’ niche. In such tissues, the details of the mechanism that determines whether stem cells differentiate or remain undifferentiated are unknown (Fuller and Spradling, 2007; Morrison and Spradling, 2008; Stine and Matunis, 2013)
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