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A role for SMAD3 in follicle-stimulating hormone production and fertility

Li Y, Schang G, Boehm U, Deng CX, Graff J, Bernard DJSMAD3 Regulates Follicle-stimulating Hormone Synthesis by Pituitary Gonadotrope Cells in Vivo. J Biol Chem. 2017 Feb 10;292(6):2301-2314. doi: 10.1074/jbc.M116.759167. Epub 2016 Dec 19.

The pituitary hormone FSH, or follicle-stimulating hormone, is an essential regulator of mammalian reproduction. In females, absence of FSH leads to sterility due to an impairment in ovarian follicle maturation.  In males, FSH regulates sperm production.  FSH synthesis is stimulated principally by two factors, gonadotropin-releasing hormone (GnRH) from the brain and activins from the pituitary. The mechanisms through which these proteins regulate FSH synthesis are incompletely resolved; however, activins appear to act via at least three proteins (SMAD3, SMAD4, and FOXL2) to stimulate production of the FSHβ subunit (Fshb) gene.  FSH is a dimeric protein with two subunits. Its β subunit is rate-limiting in the production of the mature hormone.  Whereas both in vitro and in vivo models clearly implicate SMAD4 and FOXL2 in FSH synthesis, initial reports casted doubt on an essential role for SMAD3 in vivo.  Specifically, using a conditional knockout approach, mice with a deletion in the Smad3 gene produced FSH at normal levels and were fertile. It was subsequently identified, however, that the mutation in Smad3 did not remove all of the protein. Here, we used a genetic approach to revisit SMAD3’s role in FSH synthesis by eliminating the ability of the residual SMAD3 protein to regulate the Fshb subunit gene.  The resulting mice were FSH-deficient, females were sterile, and males had low sperm counts.  This work firmly establishes an essential role for SMAD3 in FSH synthesis in vivo. 

Note: Click images to enlarge.

Figure 1: Adult mouse pituitary sections were stained with antibodies against DAPI (nuclear marker) in blue, Luteinizing hormone (LH, another hormone produced only in the gonadotropes) in green and FSH in red. Scale bar=100μm. 

Figure 2: Hypogonadism in SMAD3 deficient mice. 


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