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.

The cytoskeleton-associated protein SCHIP1 is involved in axon guidance, and is required for piriform cortex and anterior commissure development

“…However, whether schwannomin contributes to SCHIP1-mediated axon outgrowth and guidance is uncertain since SCHIP1 and schwannomin expression patterns are different during brain development (Huynh et al, 1996). In addition, Nf2 F/F ;Emx1-cre mice do not present AC defects but instead CC agenesis, which does not result from a lack of schwannomin in callosal neurons or their progenitors but in midline neural progenitor cells (Lavado et al, 2014). Schwannomin appeared to regulate guidance cue expression, whereas SCHIP1 does not and is directly involved in axon development.…”

“…Schwannomin has been shown to play roles in axon growth and guidance (Lavado et al, 2014;Schulz et al, 2010;Yamauchi et al, 2008). However, whether schwannomin contributes to SCHIP1-mediated axon outgrowth and guidance is uncertain since SCHIP1 and schwannomin expression patterns are different during brain development (Huynh et al, 1996).…”

The Caenorhabditis elegans NF2/Merlin Molecule NFM-1 Nonautonomously Regulates Neuroblast Migration and Interacts Genetically with the Guidance Cue SLT-1/Slit

“…Previous studies suggested that NF2 can nonautonomously affect axon guidance in the developing mouse brain (Lavado et al 2014). This guidance mechanism occurs through regulation of Slit2 mRNA levels, suggesting a transcriptional role of NF2 (Lavado et al 2014).…”

“…NF2/Merlin is involved in signaling pathways involving hippo, mTOR, and PI3K-Akt (Zhao et al 2007;Striedinger et al 2008;James et al 2009;Okada et al 2009). Additionally, NF2 is involved in nervous system maintenance, corpus callosum development, and axon guidance (Schulz et al 2013(Schulz et al , 2014Lavado et al 2014). In corpus callosum development, NF2 inhibits the hippo pathway component Yap.…”

“…In NF2 mutants, this inhibition is relieved, resulting in increased expression of Slit2, a secreted axon guidance cue that prevents midline crossing. This leads to defects in midline crossing of axons in the callosum (Lavado et al 2014). …”