Canonical Wnt signaling regulates patterning, differentiation and nucleogenesis in mouse hypothalamus and prethalamus.

Abstract

The hypothalamus is a small, but anatomically and functionally complex, region of the brain whose development is poorly understood. In this study, we have explored its development by studying the canonical Wntsignalling pathway, generating gain and loss of function mutations of betacaten in(Ctnnb1) in both hypothalamic and prethalamic neuroepithelium. Deletion of Ctnnb1 resulted in an anteriorized and hypoplastic hypothalamus. Posterior structures were lost or reduced, and anterior structures were expanded. In contrast, over expression of a constitutively active mutant form of Ctnnb1 resulted in severe hyperplasia of prethalamus and hypothalamus, and expanded expression of a subset of posterior and premamillary hypothalamic markers. Moderate defects in differentiation of Arx-positive GABAergic neural precursors were observed in both prethalamus and hypothalamus of Ctnnb1 loss of function mutants, while in gain of function mutants, their differentiation was completely suppressed, although markers of prethalamic progenitors were preserved. Multiple other region-specific markers, including several specific posterior hypothalamic structures, were also suppressed in Ctnnb1 gain of function mutations. Severe, region-specific defects in hypothalamic nucleogenesis were also observed in both gain and loss of function mutations of Ctnnb1. Finally, both gain and loss of function of Ctnnb1 also produced severe, cell nonautonomous disruptions of pituitary development. These findings demonstrate acentral and multifaceted role for canonical Wnt signalling in regulating growth, patterning, differentiation and nucleogenesis in multiple diencephalic regions.\n\nHighlightsO_LICanonical Wnt signalling regulates anteroposterior patterning in the hypothalamus.\nC_LIO_LICanonical Wnt signalling regulates differentiation of GABAergic neurons in both prethalamus and hypothalamus.\nC_LIO_LICanonical Wnt signalling regulates differentiation and nucleogenesis of multiple hypothalamic neuronal subtypes.\nC_LIO_LICanonical Wnt signalling in hypothalamic neuroepithelium regulates pituitary morphogenesis and differentiation.\nC_LI