| First Author | Wang H | Year | 2016 |
| Journal | Mol Cell Endocrinol | Volume | 426 |
| Pages | 113-24 | PubMed ID | 26911932 |
| Mgi Jnum | J:241189 | Mgi Id | MGI:5897963 |
| Doi | 10.1016/j.mce.2016.02.015 | Citation | Wang H, et al. (2016) A human FSHB transgene encoding the double N-glycosylation mutant (Asn(7Delta) Asn(24Delta)) FSHbeta subunit fails to rescue Fshb null mice. Mol Cell Endocrinol 426:113-24 |
| abstractText | Follicle-stimulating hormone (FSH) is a gonadotrope-derived heterodimeric glycoprotein. Both the common alpha- and hormone-specific beta subunits contain Asn-linked N-glycan chains. Recently, macroheterogeneous FSH glycoforms consisting of beta-subunits that differ in N-glycan number were identified in pituitaries of several species and subsequently the recombinant human FSH glycoforms biochemically characterized. Although chemical modification and in vitro site-directed mutagenesis studies defined the roles of N-glycans on gonadotropin subunits, in vivo functional analyses in a whole-animal setting are lacking. Here, we have generated transgenic mice with gonadotrope-specific expression of either an HFSHB(WT) transgene that encodes human FSHbeta WT subunit or an HFSHB(dgc) transgene that encodes a human FSHbeta(Asn7Delta 24Delta) double N-glycosylation site mutant subunit, and separately introduced these transgenes onto Fshb null background using a genetic rescue strategy. We demonstrate that the human FSHbeta(Asn7Delta 24Delta) double N-glycosylation site mutant subunit, unlike human FSHbeta WT subunit, inefficiently combines with the mouse alpha-subunit in pituitaries of Fshb null mice. FSH dimer containing this mutant FSHbeta subunit is inefficiently secreted with very low levels detectable in serum. Fshb null male mice expressing HFSHB(dgc) transgene are fertile and exhibit testis tubule size and sperm number similar to those of Fshb null mice. Fshb null female mice expressing the mutant, but not WT human FSHbeta subunit-containing FSH dimer are infertile, demonstrate no evidence of estrus cycles, and many of the FSH-responsive genes remain suppressed in their ovaries. Thus, HFSHB(dgc) unlike HFSHB(WT) transgene does not rescue Fshb null mice. Our genetic approach provides direct in vivo evidence that N-linked glycans on FSHbeta subunit are essential for its efficient assembly with the alpha-subunit to form FSH heterodimer in pituitary. Our studies also reveal that N-glycans on FSHbeta subunit are essential for FSH secretion and FSH in vivo bioactivity to regulate gonadal growth and physiology. |
