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

Abstract

The corpus callosum connects cerebral hemispheres and is the largest axon tract in the mammalian brain. Callosal malformations are among the most common congenital brain anomalies and are associated with a wide range of neuropsychological deficits. Crossing of the midline by callosal axons relies on a proper midline environment that harbors guidepost cells emitting guidance cues to instruct callosal axon navigation. Little is known about what controls the formation of the midline environment. We find that two components of the Hippo pathway, the tumor suppressor Nf2 (Merlin) and the transcriptional coactivator Yap (Yap1), regulate guidepost development and expression of the guidance cue Slit2 in mouse. During normal brain development, Nf2 suppresses Yap activity in neural progenitor cells to promote guidepost cell differentiation and prevent ectopic Slit2 expression. Loss of Nf2 causes malformation of midline guideposts and Slit2 upregulation, resulting in callosal agenesis. Slit2 heterozygosity and Yap deletion both restore callosal formation in Nf2 mutants. Furthermore, selectively elevating Yap activity in midline neural progenitors is sufficient to disrupt guidepost formation, upregulate Slit2 and prevent midline crossing. The Hippo pathway is known for its role in controlling organ growth and tumorigenesis. Our study identifies a novel role of this pathway in axon guidance. Moreover, by linking axon pathfinding and neural progenitor behaviors, our results provide an example of the intricate coordination between growth and wiring during brain development.

YAP activity is necessary and sufficient for basal progenitor abundance and proliferation in the developing neocortex

“…Finally, comparison of mRNA levels between a prospective gyrus vs. a prospective sulcus of developing (postnatal day (P) 2) ferret neocortex, available in a previously published transcriptome dataset (De Juan Romero et al, 2015), showed that the Yap mRNA level was higher in the oSVZ of the prospective gyrus than the prospective sulcus ( Figure S1D), consistent with the notion that a relative increase in cNPC proliferation in this germinal zone contributes to gyrus formation (Hansen et al, 2010;Reillo et al, 2011;Wang et al, 2011). Taken together, these Yap/YAP mRNA data raised the possibility that YAP may not only have a role in the proliferation of APs, as previously shown for embryonic mouse neocortex (Lavado et al, 2013;Lavado et al, 2014), but that differences in the level of active YAP may underlie the differences in the proliferative capacity of mouse vs. ferret and human BPs.…”

“…of YAP were confined to mouse brain development and concentrated on APs (Cappello et al, 2013;Lavado et al, 2013;Lavado et al, 2014;Saito et al, 2017). In contrast to these reports, the present study is focused on BPs and in this context has compared YAP expression and activity in the SVZ vs. VZ of developing neocortex of three mammals exhibiting a different extent of neocortex expansion -mouse, ferret and human.…”

“…Phosphorylated YAP (phospho-YAP) is retained in the cytoplasm, whereas dephosphorylated YAP (active YAP) translocates to the nucleus and activates the expression of genes linked to cell proliferation Zhao et al, 2010;Zhao et al, 2007;. Recent studies dissecting the roles of the cadherin family members Dchs1 and Fat4 (Cappello et al, 2013) and of the tumor suppressor neurofibromatosis 2 (Lavado et al, 2013;Lavado et al, 2014) and investigating heterotopia formation (Saito et al, 2017) in mouse brain development have reported that YAP promotes the proliferation of mouse APs. These studies, however, have not focused on a potential role of YAP in regulating the proliferation of BPs, nor have they addressed the question whether differences in YAP activity may underlie the differences in the proliferative capacity of BPs across various mammalian species in the context of the evolutionary expansion of the neocortex.…”

Hippo vs. Crab: tissue‐specific functions of the mammalian Hippo pathway

“…), whereas telencephalon‐specific Nf2 KO embryos show expansion of neural progenitors with increased nuclear YAP1/TAZ (Lavado et al . , ).…”

“…Mice heterozygous for mutated Nf2 do not develop neuronal malignancies, but homozygous Nf2 loss only in Schwann cells leads to their hyperplasia and eventually schwannomas (Giovannini et al 2000). Double loss of Nf2 plus one p53 allele drives the development of peripheral nerve sheath tumors (Robanus-Maandag et al 2004), whereas telencephalon-specific Nf2 KO embryos show expansion of neural progenitors with increased nuclear YAP1/TAZ (Lavado et al 2013(Lavado et al , 2014.…”