Abstract
The secreted molecule fibroblast growth factor 9 (FGF9) plays a critical role in testis determination in the mouse. In embryonic gonadal somatic cells it is required for maintenance of SOX9 expression, a key determinant of Sertoli cell fate. Conditional gene targeting studies have identified FGFR2 as the main gonadal receptor for FGF9 during sex determination. However, such studies can be complicated by inefficient and variable deletion of floxed alleles, depending on the choice of Cre deleter strain. Here, we report a novel, constitutive allele of Fgfr2, hobbyhorse (hob), which was identified in an ENU-based forward genetic screen for novel testis-determining loci. Fgr2hob is caused by a C to T mutation in the invariant exon 7, resulting in a polypeptide with a mis-sense mutation at position 263 (Pro263Ser) in the third extracellular immunoglobulin-like domain of FGFR2. Mutant homozygous embryos show severe limb and lung defects and, when on the sensitised C57BL/6J (B6) genetic background, undergo complete XY gonadal sex reversal associated with failure to maintain expression of Sox9. Genetic crosses employing a null mutant of Fgfr2 suggest that Fgr2hob is a hypomorphic allele, affecting both the FGFR2b and FGFR2c splice isoforms of the receptor. We exploited the consistent phenotype of this constitutive mutant by analysing MAPK signalling at the sex-determining stage of gonad development, but no significant abnormalities in mutant embryos were detected.
Highlights
Fibroblast growth factors (FGF) function in numerous processes throughout embryonic development, such as the induction and patterning of germ cell layers, body axis formation and organogenesis [1]
Previous studies of Fgfr2 function in testis determination have relied on conditional gene targeting, with the attendant variability in efficiency and site of gene ablation resulting in some phenotypic variation
Homozygous deletion of floxed Fgfr2 alleles using Sf1Cre, which is expressed primarily in somatic cells within the gonad, resulted in partial XY sex reversal, with ovotestis formation commonly observed at 15.5 dpc [12]
Summary
Fibroblast growth factors (FGF) function in numerous processes throughout embryonic development, such as the induction and patterning of germ cell layers, body axis formation and organogenesis [1]. It has been proposed that the rapid diffusion of secreted FGF9 along the long, thin gonad at around 11.5 dpc prevents any appreciable delay in the gonadal poles receiving the masculinising signal begun by expression of SRY at the centre of the gonad [9]. Any such delay may result in ovotestis or ovary development in an XY embryo due to the restricted time window that is thought to define the competence of cells to respond to SRY and its downstream effectors [10]
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