Perinatal midline astrocyte development is impaired in fibroblast growth factor 8 hypomorphic mice

Abstract

Our previous studies showed that Fgf8 mutations can cause Kallmann syndrome (KS), a form of congenital hypogonadotropic hypogonadism, in which patients do not undergo puberty and are infertile. Interestingly, some KS patients also have agenesis of the corpus callosum (ACC) suggesting that KS pathology is not limited to reproductive function. Here, we asked whether FGF8 dysfunction is the underlying cause of ACC in some KS patients. Indeed, early studies in transgenic mice with Fgf8 mutations reported the presence of failed or incomplete corpus callosum formation. Additional studies in transgenic mice showed that FGF8 function most likely prevents the prenatal elimination of glial fibrillary acidic protein (GFAP)-immunoreactive (IR) glial cells in the indusium griseum (IG) and midline zipper (MZ), two anterior-dorsal midline regions required for corpus callosum formation (i.e., between embryonic days (E) 15.5–18.5). Here, we tested the hypothesis that FGF8 function is critical for the survival of the GFAP-IR midline glial cells. First, we measured the incidence of apoptosis in the anterior-dorsal midline region in Fgf8 hypomorphic mice during embryonic corpus callosum formation. Second, we quantified the GFAP expression in the anterior-dorsal midbrain region during pre- and postnatal development, in order to study: 1) how Fgf8 hypomorphy disrupts prenatal GFAP-IR midline glial cell development, and 2) whether Fgf8 hypomorphy continues to disrupt postnatal GFAP-IR midline glial cell development. Our results indicate that perinatal FGF8 signaling is important for the timing of the onset of anterior-dorsal Gfap expression in midline glial cells suggesting that FGF8 function regulates midline GFAP-IR glial cell development, which when disrupted by Fgf8 deficiency prevents the formation of the corpus callosum. These studies provide an experimentally-based mechanistic explanation as to why corpus callosum formation may fail in KS patients with deficits in FGF signaling.