Altered GLI3 and FGF8 signaling underlies acrocallosal syndrome phenotypes in Kif7 depleted mice.

Acrocallosal syndrome (ACLS) is a rare genetic disorder characterized by agenesis or hypoplasia of corpus callosum (CC), polydactyly, craniofacial dysmorphism and severe intellectual deficiency. We previously identified KIF7, a key ciliary component of the Sonic hedgehog (SHH) pathway, as being a causative gene for this syndrome, thus including ACLS in the group of ciliopathies. In both humans and mice, KIF7 depletion leads to abnormal GLI3 processing and over-activation of SHH target genes. To understand the pathological mechanisms involved in CC defects in this syndrome, we took advantage of a previously described Kif7-/- mouse model to demonstrate that in addition to polydactyly and neural tube closure defects, these mice present CC agenesis with characteristic Probst bundles, thus recapitulating major ACLS features. We show that CC agenesis in these mice is associated with specific patterning defects of the cortical septum boundary leading to altered distribution of guidepost cells required to guide the callosal axons through the midline. Furthermore, by crossing Kif7-/- mice with Gli3Δ699 mice exclusively producing the repressive isoform of GLI3 (GLI3R), we demonstrate that decreased GLI3R signaling is fully responsible for the ACLS features in these mice, as all phenotypes are rescued by increasing GLI3R activity. Moreover, we show that increased FGF8 signaling is responsible in part for CC defects associated to KIF7 depletion, as modulating FGF8 signaling rescued CC formation anteriorly in Kif7-/- mice. Taken together our data demonstrate that ACLS features rely on defective GLI3R and FGF8 signaling.

Auditory interhemispheric transfer in relation to patterns of partial agenesis and hypoplasia of the corpus callosum in spina bifida meningomyelocele.

Spina bifida meningomyelocele with hydrocephalus (SBM) is commonly associated with anomalies of the corpus callosum (CC). We describe MRI patterns of regional CC agenesis and relate CC anomalies to functional laterality based on a dichotic listening test in 90 children with SBM and 27 typically developing controls. Many children with SBM (n = 40) showed regional CC anomalies in the form of agenesis of the rostrum and/or splenium, and a smaller number (n = 20) showed hypoplasia (thinning) of all CC regions (rostrum, genu, body, and splenium). The expected right ear advantage (REA) was exhibited by normal controls and children with SBM having a normal or hypoplastic splenium. It was not shown by children with SBM who were left handed, missing a splenium, or had a higher level spinal cord lesion. Perhaps the right hemisphere of these children is more involved in processing some aspects of linguistic stimuli.