Abstract
Holoprosencephaly (HPE) is defined as the incomplete separation of the two cerebral hemispheres. The pathology of HPE is variable and, based on the severity of the defect, HPE is divided into alobar, semilobar, and lobar. Using a novel hypomorphic Six3 allele, we demonstrate in mice that variability in Six3 dosage results in different HPE phenotypes. Furthermore, we show that whereas the semilobar phenotype results from severe downregulation of Shh expression in the rostral diencephalon ventral midline, the alobar phenotype is caused by downregulation of Foxg1 expression in the anterior neural ectoderm. Consistent with these results, in vivo activation of the Shh signaling pathway rescued the semilobar phenotype but not the alobar phenotype. Our findings show that variations in Six3 dosage result in different forms of HPE.
Highlights
Incomplete separation of the cerebral hemispheres during embryonic development causes holoprosencephaly (HPE)
Using a novel hypomorphic Six3 allele, we demonstrate that variability in Six3 dosage results in different HPE phenotypes
We show that while the semilobar phenotype results from severe downregulation of Shh expression in the rostral diencephalon ventral midline, the alobar phenotype is caused by downregulation of Foxg1 expression in the anterior neural ectoderm
Summary
Incomplete separation of the cerebral hemispheres during embryonic development causes holoprosencephaly (HPE). Mutations in any of at least nine genes involved in the Shh-signaling pathway can cause congenital HPE in humans (Geng and Oliver, 2009; Roessler and Muenke, 2010). The Shh-signaling pathway accounts for only 17% of familial HPE (Cohen, 2006). Mutations in SIX3, which account for approximately 1.3% of HPE cases exemplify this phenomenon (Cohen, 2006). In the case of SIX3, mutations are associated with defects ranging from alobar HPE (cyclopia) to microforms of HPE (e.g., single medial incisor) (Lacbawan et al, 2009; Muenke and Cohen, 2000). HPE patients with normal parents that carry their same mutation have been reported (Ribeiro et al, 2006)
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