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

Elizabeth A. Newman, Dan Wu, Makoto Mark Taketo, Jiangyang Zhang, Seth Blackshaw

Research output: Contribution to journalArticle

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 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.

Original languageEnglish (US)
JournalDevelopmental Biology
DOIs
StateAccepted/In press - Jan 1 2018

Fingerprint

Hypothalamus
Wnt Signaling Pathway
Mutation
beta Catenin
Hyperplasia
Brain
Growth

ASJC Scopus subject areas

  • Molecular Biology
  • Developmental Biology
  • Cell Biology

Cite this

Canonical Wnt signaling regulates patterning, differentiation and nucleogenesis in mouse hypothalamus and prethalamus. / Newman, Elizabeth A.; Wu, Dan; Taketo, Makoto Mark; Zhang, Jiangyang; Blackshaw, Seth.

In: Developmental Biology, 01.01.2018.

Research output: Contribution to journalArticle

@article{7bc898f3a54b49bd842fc61b3da379c0,
title = "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 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.",
author = "Newman, {Elizabeth A.} and Dan Wu and Taketo, {Makoto Mark} and Jiangyang Zhang and Seth Blackshaw",
year = "2018",
month = "1",
day = "1",
doi = "10.1016/j.ydbio.2018.07.021",
language = "English (US)",
journal = "Developmental Biology",
issn = "0012-1606",
publisher = "Academic Press Inc.",

}

TY - JOUR

T1 - Canonical Wnt signaling regulates patterning, differentiation and nucleogenesis in mouse hypothalamus and prethalamus

AU - Newman, Elizabeth A.

AU - Wu, Dan

AU - Taketo, Makoto Mark

AU - Zhang, Jiangyang

AU - Blackshaw, Seth

PY - 2018/1/1

Y1 - 2018/1/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85051039186&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85051039186&partnerID=8YFLogxK

U2 - 10.1016/j.ydbio.2018.07.021

DO - 10.1016/j.ydbio.2018.07.021

M3 - Article

C2 - 30063881

AN - SCOPUS:85051039186

JO - Developmental Biology

JF - Developmental Biology

SN - 0012-1606

ER -