Abstract
Reduced fibroblast growth factor (FGF) signaling from the mid-hindbrain or isthmus organizer (IsO) during early embryonic development results in hypoplasia of the midbrain and cerebellar vermis. We previously reported evidence for reduced Fgf8 expression and FGF signaling in the mid-hindbrain region of embryos heterozygous for Chd7, the gene mutated in CHARGE (Coloboma, Heart defects, choanal Atresia, Retarded growth and development, Genitourinary anomalies and Ear defects) syndrome. However, Chd7+/− animals only exhibit mild cerebellar vermis anomalies. As homozygous deletion of Chd7 is embryonic lethal, we conditionally deleted Chd7 from the early embryonic mid-hindbrain region to identify the function of CHD7 in mid-hindbrain development. Using a combination of high resolution structural MRI and histology, we report striking midbrain and cerebellar vermis hypoplasia in the homozygous conditional mutants. We show that cerebellar vermis hypoplasia is associated with reduced embryonic Fgf8 expression and an expanded roof plate in rhombomere 1 (r1). These findings identify an essential role for Chd7 in regulating mid-hindbrain development via Fgf8.
Highlights
The mammalian cerebellum consists of a medial vermis, flanked by two hemispheres
The present study follows from our observation of mildly reduced Fgf8 expression in Chd7+/− embryos (Yu et al, 2013), that was found to be insufficient to fully phenocopy the striking cerebellar vermis hypoplasia observed in mutants with stronger reductions in fibroblast growth factor (FGF) signaling
Fgf8 expression was strongly reduced in Chd7−/− embryos, the effect of this reduction in Fgf8 expression on cerebellar vermis development could not be studied due to the embryonic lethality of these embryos (Yu et al, 2013)
Summary
The mammalian cerebellum consists of a medial vermis, flanked by two hemispheres. Genetic lineage tracing studies in the mouse have shown that the cerebellar vermis is derived from a small group of progenitor cells located in the most anterior part of rhombomere 1 (r1; Sgaier et al, 2005). The specification, maintenance and/or expansion of these progenitors is regulated by the fibroblast growth factor (FGF) signaling pathway (Joyner et al, 2000; Chi et al, 2003; Sato et al, 2004; Sgaier et al, 2005; Basson et al, 2008). We have previously shown that the level of FGF signaling from the IsO has to be tightly controlled. Whereas increased signaling results in an expanded vermis (Yu et al, 2011), reduced FGF signaling leads to cerebellar vermis hypoplasia (Basson et al, 2008)
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