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

Developmental biology

Seth Blackshaw^1,3,4,5,6¹  Jiangyang Zhang^8²  Makoto Mark Taketo^7³  Dan Wu^2⁴  Elizabeth A. Newman^1⁸ 

[1] Center for Human Systems Biology, Johns Hopkins University School of Medicine, Baltimore, MD, USA^5;Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA^4;Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, MD, USA^3;Department of Radiology, Johns Hopkins University School of Medicine, Baltimore, MD, USA^2;Department of Radiology, NYU Langone School of Medicine, New York, NY, USA^8;Division of Experimental Therapeutics, Graduate School of Medicine, Kyoto University, Kyoto, Japan^7;Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, USA^6;Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, USA^1

关键词: ArcN;    arcuate nucleus;    EmThal;    thalamic eminence;    ID;    intrahypothalamic diagonal;    MM;    mamillary hypothalamus;    PMN;    premamillary hypothalamus;    PrThal;    prethalamus;    PvN;    paraventricular nucleus;    SMN;    supramammilary hypothalamus;    SCN;    suprachiasmatic nucleus;    VMH;    ventromedial hypothalamus;   

DOI  :  10.1016/j.ydbio.2018.07.021

学科分类：生物科学（综合）

来源: Academic Press

【 摘 要 】

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 Wnt signaling pathway, generating gain and loss of function mutations of beta-catenin (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, overexpression 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, non-cell autonomous disruptions of pituitary development. These findings demonstrate a central and multifaceted role for canonical Wnt signaling in regulating growth, patterning, differentiation and nucleogenesis in multiple diencephalic regions.

【 授权许可】

CC BY