Hierarchical differentiation competence in response to retinoic acid ensures stem cell maintenance during mouse spermatogenesis.

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.

• Authors: Kanako Ikami, Moe Tokue, Ryo Sugimoto, Chiyo Noda, Satoru Kobayashi, Kenshiro Hara, Shosei Yoshida
• Journal: Development (Cambridge, England) (Development) Vol. 142 Issue 9 Pg. 1582-92 (May 01 2015) ISSN: 1477-9129 [Electronic] England
• PMID: 25858458 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2015. Published by The Company of Biologists Ltd.

Chemical References

• Basic Helix-Loop-Helix Transcription Factors
• Gfra1 protein, mouse
• Glial Cell Line-Derived Neurotrophic Factor Receptors
• Nerve Tissue Proteins
• Neurog3 protein, mouse
• Receptors, Retinoic Acid
• retinoic acid receptor gamma
• Tretinoin

Topics

• Animals
• Basic Helix-Loop-Helix Transcription Factors (metabolism)
• Cell Differentiation (drug effects, physiology)
• Fluorescent Antibody Technique
• Glial Cell Line-Derived Neurotrophic Factor Receptors (metabolism)
• In Situ Hybridization
• Male
• Mice
• Mice, Transgenic
• Nerve Tissue Proteins (metabolism)
• Real-Time Polymerase Chain Reaction
• Receptors, Retinoic Acid (metabolism)
• Spermatogenesis (physiology)
• Stem Cells (physiology)
• Tretinoin (pharmacology)
• Vitamin A Deficiency (metabolism)