Grainyhead-like 3 (Grhl3) deficiency in brain leads to altered locomotor activity and decreased anxiety-like behaviors in aged mice

Sebastian Dworkin, Alana Auden, Darren D. Partridge, Maria Daglas, Robert L. Medcalf, Theo Mantamadiotis, Smitha R. Georgy, Charbel Darido, Stephen M. Jane, Stephen B. Ting

Research output: Contribution to journalArticleResearchpeer-review

Abstract

The highly conserved Grainyhead-like (Grhl) family of transcription factors, comprising three members in vertebrates (Grhl1-3), play critical regulatory roles during embryonic development, cellular proliferation, and apoptosis. Although loss of Grhl function leads to multiple neural abnormalities in numerous animal models, a comprehensive analysis of Grhl expression and function in the mammalian brain has not been reported. Here they show that only Grhl3 expression is detectable in the embryonic mouse brain; particularly within the habenula, an organ known to modulate repressive behaviors. Using both Grhl3-knockout mice (Grhl3-/-), and brain-specific conditional deletion of Grhl3 in adult mice (Nestin-Cre/Grhl3flox/flox), they performed histological expression analyses and behavioral tests to assess long-term effects of Grhl3 loss on motor co-ordination, spatial memory, anxiety, and stress. They found that complete deletion of Grhl3 did not lead to noticeable structural or cell-intrinsic defects in the embryonic brain; however, aged Grhl3 conditional knockout (cKO) mice showed enlarged lateral ventricles and displayed marked changes in motor function and behaviors suggestive of decreased fear and anxiety. They conclude that loss of Grhl3 in the brain leads to significant alterations in locomotor activity and decreased self-inhibition, and as such, these mice may serve as a novel model of human conditions of impulsive behavior or hyperactivity.

Original languageEnglish
Pages (from-to)775-788
Number of pages14
JournalDevelopmental Neurobiology
Volume77
Issue number6
DOIs
Publication statusPublished - Jun 2017

Keywords

  • Cre-mediated deletion
  • Grainyhead-like
  • Habenula

Cite this

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title = "Grainyhead-like 3 (Grhl3) deficiency in brain leads to altered locomotor activity and decreased anxiety-like behaviors in aged mice",
abstract = "The highly conserved Grainyhead-like (Grhl) family of transcription factors, comprising three members in vertebrates (Grhl1-3), play critical regulatory roles during embryonic development, cellular proliferation, and apoptosis. Although loss of Grhl function leads to multiple neural abnormalities in numerous animal models, a comprehensive analysis of Grhl expression and function in the mammalian brain has not been reported. Here they show that only Grhl3 expression is detectable in the embryonic mouse brain; particularly within the habenula, an organ known to modulate repressive behaviors. Using both Grhl3-knockout mice (Grhl3-/-), and brain-specific conditional deletion of Grhl3 in adult mice (Nestin-Cre/Grhl3flox/flox), they performed histological expression analyses and behavioral tests to assess long-term effects of Grhl3 loss on motor co-ordination, spatial memory, anxiety, and stress. They found that complete deletion of Grhl3 did not lead to noticeable structural or cell-intrinsic defects in the embryonic brain; however, aged Grhl3 conditional knockout (cKO) mice showed enlarged lateral ventricles and displayed marked changes in motor function and behaviors suggestive of decreased fear and anxiety. They conclude that loss of Grhl3 in the brain leads to significant alterations in locomotor activity and decreased self-inhibition, and as such, these mice may serve as a novel model of human conditions of impulsive behavior or hyperactivity.",
keywords = "Cre-mediated deletion, Grainyhead-like, Habenula",
author = "Sebastian Dworkin and Alana Auden and Partridge, {Darren D.} and Maria Daglas and Medcalf, {Robert L.} and Theo Mantamadiotis and Georgy, {Smitha R.} and Charbel Darido and Jane, {Stephen M.} and Ting, {Stephen B.}",
year = "2017",
month = "6",
doi = "10.1002/dneu.22469",
language = "English",
volume = "77",
pages = "775--788",
journal = "Developmental Neurobiology",
issn = "1932-8451",
publisher = "John Wiley & Sons",
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Grainyhead-like 3 (Grhl3) deficiency in brain leads to altered locomotor activity and decreased anxiety-like behaviors in aged mice. / Dworkin, Sebastian; Auden, Alana; Partridge, Darren D.; Daglas, Maria; Medcalf, Robert L.; Mantamadiotis, Theo; Georgy, Smitha R.; Darido, Charbel; Jane, Stephen M.; Ting, Stephen B.

In: Developmental Neurobiology, Vol. 77, No. 6, 06.2017, p. 775-788.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Grainyhead-like 3 (Grhl3) deficiency in brain leads to altered locomotor activity and decreased anxiety-like behaviors in aged mice

AU - Dworkin, Sebastian

AU - Auden, Alana

AU - Partridge, Darren D.

AU - Daglas, Maria

AU - Medcalf, Robert L.

AU - Mantamadiotis, Theo

AU - Georgy, Smitha R.

AU - Darido, Charbel

AU - Jane, Stephen M.

AU - Ting, Stephen B.

PY - 2017/6

Y1 - 2017/6

N2 - The highly conserved Grainyhead-like (Grhl) family of transcription factors, comprising three members in vertebrates (Grhl1-3), play critical regulatory roles during embryonic development, cellular proliferation, and apoptosis. Although loss of Grhl function leads to multiple neural abnormalities in numerous animal models, a comprehensive analysis of Grhl expression and function in the mammalian brain has not been reported. Here they show that only Grhl3 expression is detectable in the embryonic mouse brain; particularly within the habenula, an organ known to modulate repressive behaviors. Using both Grhl3-knockout mice (Grhl3-/-), and brain-specific conditional deletion of Grhl3 in adult mice (Nestin-Cre/Grhl3flox/flox), they performed histological expression analyses and behavioral tests to assess long-term effects of Grhl3 loss on motor co-ordination, spatial memory, anxiety, and stress. They found that complete deletion of Grhl3 did not lead to noticeable structural or cell-intrinsic defects in the embryonic brain; however, aged Grhl3 conditional knockout (cKO) mice showed enlarged lateral ventricles and displayed marked changes in motor function and behaviors suggestive of decreased fear and anxiety. They conclude that loss of Grhl3 in the brain leads to significant alterations in locomotor activity and decreased self-inhibition, and as such, these mice may serve as a novel model of human conditions of impulsive behavior or hyperactivity.

AB - The highly conserved Grainyhead-like (Grhl) family of transcription factors, comprising three members in vertebrates (Grhl1-3), play critical regulatory roles during embryonic development, cellular proliferation, and apoptosis. Although loss of Grhl function leads to multiple neural abnormalities in numerous animal models, a comprehensive analysis of Grhl expression and function in the mammalian brain has not been reported. Here they show that only Grhl3 expression is detectable in the embryonic mouse brain; particularly within the habenula, an organ known to modulate repressive behaviors. Using both Grhl3-knockout mice (Grhl3-/-), and brain-specific conditional deletion of Grhl3 in adult mice (Nestin-Cre/Grhl3flox/flox), they performed histological expression analyses and behavioral tests to assess long-term effects of Grhl3 loss on motor co-ordination, spatial memory, anxiety, and stress. They found that complete deletion of Grhl3 did not lead to noticeable structural or cell-intrinsic defects in the embryonic brain; however, aged Grhl3 conditional knockout (cKO) mice showed enlarged lateral ventricles and displayed marked changes in motor function and behaviors suggestive of decreased fear and anxiety. They conclude that loss of Grhl3 in the brain leads to significant alterations in locomotor activity and decreased self-inhibition, and as such, these mice may serve as a novel model of human conditions of impulsive behavior or hyperactivity.

KW - Cre-mediated deletion

KW - Grainyhead-like

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U2 - 10.1002/dneu.22469

DO - 10.1002/dneu.22469

M3 - Article

VL - 77

SP - 775

EP - 788

JO - Developmental Neurobiology

JF - Developmental Neurobiology

SN - 1932-8451

IS - 6

ER -