Agenesis of the Corpus Callosum Due to Defective Glial Wedge Formation in Lhx2 Mutant Mice

Abstract

Establishment of the corpus callosum involves coordination between callosal projection neurons and multiple midline structures, including the glial wedge (GW) rostrally and hippocampal commissure caudally. GW defects have been associated with agenesis of the corpus callosum (ACC). Here we show that conditional Lhx2 inactivation in cortical radial glia using Emx1-Cre or Nestin-Cre drivers results in ACC. The ACC phenotype was characterized by aberrant ventrally projecting callosal axons rather than Probst bundles, and was 100% penetrant on 2 different mouse strain backgrounds. Lhx2 inactivation in postmitotic cortical neurons using Nex-Cre mice did not result in ACC, suggesting that the mutant phenotype was not autonomous to the callosal projection neurons. Instead, ACC was associated with an absent hippocampal commissure and a markedly reduced to absent GW. Expression studies demonstrated strong Lhx2 expression in the normal GW and in its radial glial progenitors, with absence of Lhx2 resulting in normal Emx1 and Sox2 expression, but premature exit from the cell cycle based on EdU-Ki67 double labeling. These studies define essential roles for Lhx2 in GW, hippocampal commissure, and corpus callosum formation, and suggest that defects in radial GW progenitors can give rise to ACC.

Lhx2 Is an Essential Factor for Retinal Gliogenesis and Notch Signaling

“…9b). Lhx2 also bound to the gliogenic bHLH factor Hes5 and the early glial markers Slc1a3 and Car2 (Blackshaw et al, 2004) directly at this time point (Fig. 9b).…”

“…Single color in situ hybridization was performed as described previously (Blackshaw et al, 2004). Sequences for RNA probes targeting Rax and Fgf15 have been described previously (Shimogori et al, 2010).…”

“…Gene expression differences between wild-type and mutant samples, significance (p-value) and false discovery rate (FDR) were computed using the generalized linear models based EdgeR (Robinson et al, 2010). Cellular expression data for retinal genes was compiled from the literature, relying heavily on large-scale gene expression profiling studies Blackshaw et al, 2004;Siegert et al, 2012;Macosko et al, 2015). All data generated from RNA-Seq studies including raw unprocessed datasets have been deposited into the Gene Expression Omnibus repository of the NCBI and have been released publicly under the series entry accession #GSE75889.…”

“…1f,g, yellow arrowheads, k,l ) as well as a small cohort of amacrine cells in the postnatal retina (Fig. 1f-j, white arrows;Balasubramanian et al, 2014). Lhx2 expression in the medial inner nuclear layer (INL) of the retina is restricted to MG by postnatal day (P)7 (Fig.…”

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

“…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.…”