Gli3 is required in Emx1+ progenitors for the development of the corpus callosum

Abstract

The corpus callosum (CC) is the largest commissure in the forebrain and mediates the transfer of sensory, motor and cognitive information between the cerebral hemispheres. During CC development, a number of strategically located glial and neuronal guidepost structures serve to guide callosal axons across the midline at the corticoseptal boundary (CSB). Correct positioning of these guideposts requires the Gli3 gene, mutations of which result in callosal defects in humans and mice. However, as Gli3 is widely expressed during critical stages of forebrain development, the precise temporal and spatial requirements for Gli3 function in callosal development remain unclear. Here, we used a conditional mouse mutant approach to inactivate Gli3 in specific regions of the developing telencephalon in order to delineate the domain(s) in which Gli3 is required for normal development of the corpus callosum. Inactivation of Gli3 in the septum or in the medial ganglionic eminence had no effect on CC formation, however Gli3 inactivation in the developing cerebral cortex led to the formation of a severely hypoplastic CC at E18.5 due to a severe disorganization of midline guideposts. Glial wedge cells translocate prematurely and Slit1/2 are ectopically expressed in the septum. These changes coincide with altered Fgf and Wnt/β-catenin signalling during CSB formation. Collectively, these data demonstrate a crucial role for Gli3 in cortical progenitors to control CC formation and indicate how defects in CSB formation affect the positioning of callosal guidepost cells.

The tumor suppressor Nf2 regulates corpus callosum development by inhibiting the transcriptional coactivator Yap

“…S4A-F′). Gli3 and Fgf8 are required for corticoseptal boundary patterning and callosal formation (Amaniti et al, 2013;Magnani et al, 2014;Moldrich et al, 2010). Their expression and that of Sprouty1, a target of Fgf signaling, appeared normal in Nf2 mutants (supplementary material Fig.…”

“…Nf2 mutants closely resemble Gli3 hypomorphic and conditional knockout mutants, which have overextended GW processes, fewer Calretinin + guidepost neurons and increased Slit2 levels (Amaniti et al, 2013;Magnani et al, 2014). However, it does not seem that Nf2 mutant phenotypes are caused by altered Gli3 function.…”

“…However, it does not seem that Nf2 mutant phenotypes are caused by altered Gli3 function. First, Gli3 mutations lead to altered Fgf and Wnt signaling at the corticoseptal boundary and defective midline patterning (Amaniti et al, 2013;Magnani et al, 2014), whereas Fgf, Wnt signaling and midline patterning are unperturbed in Nf2 mutants. Second, unlike in Nf2 mutants, Slit2 deletion in Gli3 hypomorphic mutants does not restore the corpus callosum, consistent with Gli3 hypomorphic mutants having an earlier and broader midline patterning defect.…”

“…Although it has long been recognized that the environment which callosal axons traverse is crucial for their pathfinding, how this environment is shaped is not well understood. Despite recent progress (Amaniti et al, 2013;Benadiba et al, 2012;Chinn et al, 2014;Magnani et al, 2014;Piper et al, 2009a;Shu et al, 2003a,b;Smith et al, 2006;Unni et al, 2012), our knowledge of what regulates the development of guideposts and expression of guidance molecules remains limited.…”

Contralateral targeting of the corpus callosum

“…Nuclear factor I (Nfi), GLI-Kruppel family member GLI3 (Gli3) and Fibroblast growth factor receptor 1 (Fgfr1) signalling) to specify and migrate normally, and thus some knockout animals lacking these genes show defects in these populations and subsequently altered callosal development (Shu et al, 2003c;Steele-Perkins et al, 2005;Smith et al, 2006;Amaniti et al, 2013;Magnani et al, 2014).…”