Editors' ChoiceDevelopmental Biology

Yap Inhibits Axon Migration

Sci. Signal.  28 Oct 2014:
Vol. 7, Issue 349, pp. ec305
DOI: 10.1126/scisignal.aaa1521

The corpus callosum is a large bundle of axons that connects the right and left hemispheres of the brain. During development axons are guided across the callosum by various physical and molecular cues, such as the chemorepellent protein Slit2. Among the cells that produce guidance factors are the neural guidepost cells, which reside near the midline of the brain where the callosum forms. The scaffolding protein Nf2 (also known as Merlin) can inhibit the transcriptional coactivator Yap as part of the Hippo signaling pathway, best known for regulating cell proliferation and controlling organ size. Conditional knockout of Nf2 in the developing forebrain in mice (Nf2F/F; Emx1-Cre mice) disrupts callosal development. Lavado et al. discovered that Nf2 and Yap regulated the development and function of guidepost cells. Nf2 was present in midline neural progenitor cells that give rise to guidepost cells. Although, the gross morphology of the midline was normal in Nf2F/F; Emx1-Cre mice, neural progenitor cells failed to retract processes attached to the midline and guidepost cells did not properly differentiate. The expression of Slit2 was increased in midline cells in Nf2F/F; Emx1-Cre mice. Overexpression of Slit2 in the brains of wild-type mice resulted in the accumulation of tangled axons. Heterozygous deletion of Slit2 or conditional deletion of Yap in the forebrain restored formation of the callosum in Nf2F/F; Emx1-Cre mice. Overexpression of Yap in midline neural progenitor cells caused callosal and guidepost cell phenotypes similar to those in Nf2F/F; Emx1-Cre mice. Thus, these data indicate that Nf2 inhibits the expression of Slit2 in midline cells and limits the activation of Yap, promoting formation of guidepost cells and enabling callosal axons to cross the midline.

A. Lavado, M. Ware, J. Paré, X. Cao, The tumor suppressor Nf2 regulates corpus callosum development by inhibiting the transcriptional coactivator Yap. Development 141, 4182–4193 (2014). [Abstract] [Full Text]