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How vitamin A controls the differentiation of male germ cells

Figure (A) When retinoic acid (ATRA) is not available to activate the RAR / RXR nuclear receptor heterodimers, SALL4A expression is off. Under these conditions, the transcription repressor ZBTB16 binds to the KIT gene promoter, blocking the access to SOHLH1 transcription factor and preventing expression of KIT. Spermatogonia (ZBTB16-positive, in red) remain "undifferentiated" (KIT-negative, in green). (B) In the presence of ATRA (yellow triangle), RAR / RXR heterodimers located on the Sall4a gene promoter are activated. They induce the production of SALL4A, which has the ability to interact with ZBTB16 and drives it away from the promoter of KIT gene, enabling the action of SOHLH1 and therefore KIT expression. Spermatogonia (ZBTB16-positive, in red) switch to the "differentiated" state (KIT-positive, in green).

Retinoic Acid Receptors Control Spermatogonia Cell-Fate and Induce Expression of the SALL4A Transcription Factor.

Gely-Pernot A(1), Raverdeau M(1), Teletin M(2), Vernet N(1), Féret B(1), Klopfenstein M(1), Dennefeld C(1), Davidson I(1), Benoit G(3), Mark M(2), Ghyselinck NB(1).

PLoS Genet Oct. 1, 2015


Oct. 1, 2015

The team of Norbert B. Ghyselinck and Manuel Mark has discovered one of the mechanisms by which the active metabolite of vitamin A, retinoic acid (ATRA), controls the expression of KIT, a membrane receptor essential for differentiation of germ cells and the expression of which is often dysregulated in testicular cancers. The researchers further demonstrate that germ cells devoid of ATRA nuclear receptors normally progress through meiosis and differentiate into spermatozoa. This unexpected discovery means that the action of ATRA on meiosis is of paracrine nature. This study is published on October 1st in the journal PLoS Genetics.

Spermatogenesis is the process by which stem cells, called spermatogonia, differentiate, then undergoe meiosis and give rise to spermatozoa. It is established for almost a century that vitamin A is essential for spermatogenesis; but its mechanism of action in this process remains largely unknown.

 

In general, vitamin A is transformed into retinoic acid (ATRA) locally, at the tissue level, in order to exert its biological effects. In the nucleus of cells, ATRA binds to nuclear receptors called RAR and RXR, which activates the transcription of genes located near DNA sequences of gene regulation (called RARE) on which RAR and RXR are fixed. To identify the stages of spermatogenesis that actually require ATRA and discover the molecular cascades acting downstream of ATRA, the team of Norbert B. Ghyselinck and Manuel Mark used a genetic approach of targeted mutagenesis in mice to inactivate all the genes encoding RAR or RXR in spermatogonia.

 

Their study shows that the phenotypes of testicular degeneration induced by the lack of RAR or RXR are identical in their proceedings, their characteristics and their outcomes. They conclude that RAR / RXR dimers represent the functional units of the ATRA signaling pathway that allows undifferentiated spermatogonia to engage in the differentiation pathway leading to meiotic cells. The researchers also identified and characterized a functional RARE sequence in the pluripotency gene Sall4, responsible for the expression of Sall4A protein in spermatogonia when ATRA is present. This is an important finding since it provides a model explaining the effects of ATRA on spermatogonia differentiation, notably through the control by Sall4A of KIT synthesis, a tyrosine kinase membrane receptor, without which spermatogenesis is inhibited and the expression of which is altered in seminomas, a common form of testicular cancer (Figure). This study also shows that germ cells devoid of RAR or RXR undergo properly all the stages of spermatogenesis following spermatogonia differentiation, including meiosis. This last observation is totally unexpected because it goes against the dogma that signaling by RAR / RXR in germ cells is the intrinsic key governing the entry into meiosis.

 

This work opens up new perspectives in understanding the signaling pathway of ATRA, a pleiotropic compound involved in the regulation of many genes networks required for reproduction but also for embryonic development, differentiation of many cell types, homeostasis and metabolism.

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