Engrailed-2 (En2) deletion produces multiple neurodevelopmental defects in monoamine systems, forebrain structures and neurogenesis and behavior

Matthieu Genestine, Lulu Lin, Madel Durens, Yan Yan, Yiqin Jiang, Smrithi Prem, Kunal Bailoor, Brian Kelly, Patricia K. Sonsalla, Paul G. Matteson, Jill L Silverman, Jacqueline Crawley, James H. Millonig, Emanuel DiCicco-Bloom

Research output: Contribution to journalArticle

21 Citations (Scopus)

Abstract

Many genes involved in brain development have been associated with human neurodevelopmental disorders, but underlying pathophysiological mechanisms remain undefined. Human genetic and mouse behavioral analyses suggest that ENGRAILED-2 (EN2) contributes to neurodevelopmental disorders, especially autism spectrum disorder. In mouse, En2 exhibits dynamic spatiotemporal expression in embryonic mid-hindbrain regions where monoamine neurons emerge. Considering their importance in neuropsychiatric disorders, we characterized monoamine systems in relation to forebrain neurogenesis in En2- knockout (En2-KO) mice. Transmitter levels of serotonin, dopamine and norepinephrine (NE) were dysregulated from Postnatal day 7 (P7) to P21 in En2-KO, though NE exhibited the greatest abnormalities. While NE levels were reduced ~35% in forebrain, they were increased 40-75% in hindbrain and cerebellum, and these patterns paralleled changes in locus coeruleus (LC) fiber innervation, respectively. Although En2 promoter was active in Embryonic day 14.5-15.5 LC neurons, expression diminished thereafter and gene deletion did not alter brainstem NE neuron numbers. Significantly, in parallel with reduced NE levels, En2-KO forebrain regions exhibited reduced growth, particularly hippocampus, where P21 dentate gyrus granule neurons were decreased 16%, suggesting abnormal neurogenesis. Indeed, hippocampal neurogenic regions showed increased cell death (+77%) and unexpectedly, increased proliferation. Excess proliferation was restricted to early Sox2/Tbr2 progenitors whereas increased apoptosis occurred in differentiating (Dcx) neuroblasts, accompanied by reduced newborn neuron survival. Abnormal neurogenesis may reflect NE deficits because intra-hippocampal injections of β-adrenergic agonists reversed cell death. These studies suggest that disruption of hindbrain patterning genes can alter monoamine system development and thereby produce forebrain defects that are relevant to human neurodevelopmental disorders.

Original languageEnglish (US)
Pages (from-to)5805-5827
Number of pages23
JournalHuman Molecular Genetics
Volume24
Issue number20
DOIs
StatePublished - Jun 5 2015

Fingerprint

Neurogenesis
Prosencephalon
Norepinephrine
Rhombencephalon
Neurons
Locus Coeruleus
Cell Death
Adrenergic Agonists
Dentate Gyrus
Gene Deletion
Medical Genetics
Knockout Mice
Cerebellum
Genes
Brain Stem
Hippocampus
Dopamine
Serotonin
Apoptosis
Injections

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)
  • Molecular Biology

Cite this

Engrailed-2 (En2) deletion produces multiple neurodevelopmental defects in monoamine systems, forebrain structures and neurogenesis and behavior. / Genestine, Matthieu; Lin, Lulu; Durens, Madel; Yan, Yan; Jiang, Yiqin; Prem, Smrithi; Bailoor, Kunal; Kelly, Brian; Sonsalla, Patricia K.; Matteson, Paul G.; Silverman, Jill L; Crawley, Jacqueline; Millonig, James H.; DiCicco-Bloom, Emanuel.

In: Human Molecular Genetics, Vol. 24, No. 20, 05.06.2015, p. 5805-5827.

Research output: Contribution to journalArticle

Genestine, M, Lin, L, Durens, M, Yan, Y, Jiang, Y, Prem, S, Bailoor, K, Kelly, B, Sonsalla, PK, Matteson, PG, Silverman, JL, Crawley, J, Millonig, JH & DiCicco-Bloom, E 2015, 'Engrailed-2 (En2) deletion produces multiple neurodevelopmental defects in monoamine systems, forebrain structures and neurogenesis and behavior', Human Molecular Genetics, vol. 24, no. 20, pp. 5805-5827. https://doi.org/10.1093/hmg/ddv301
Genestine, Matthieu ; Lin, Lulu ; Durens, Madel ; Yan, Yan ; Jiang, Yiqin ; Prem, Smrithi ; Bailoor, Kunal ; Kelly, Brian ; Sonsalla, Patricia K. ; Matteson, Paul G. ; Silverman, Jill L ; Crawley, Jacqueline ; Millonig, James H. ; DiCicco-Bloom, Emanuel. / Engrailed-2 (En2) deletion produces multiple neurodevelopmental defects in monoamine systems, forebrain structures and neurogenesis and behavior. In: Human Molecular Genetics. 2015 ; Vol. 24, No. 20. pp. 5805-5827.
@article{52b9d576ec694f78987dc6192aa51da8,
title = "Engrailed-2 (En2) deletion produces multiple neurodevelopmental defects in monoamine systems, forebrain structures and neurogenesis and behavior",
abstract = "Many genes involved in brain development have been associated with human neurodevelopmental disorders, but underlying pathophysiological mechanisms remain undefined. Human genetic and mouse behavioral analyses suggest that ENGRAILED-2 (EN2) contributes to neurodevelopmental disorders, especially autism spectrum disorder. In mouse, En2 exhibits dynamic spatiotemporal expression in embryonic mid-hindbrain regions where monoamine neurons emerge. Considering their importance in neuropsychiatric disorders, we characterized monoamine systems in relation to forebrain neurogenesis in En2- knockout (En2-KO) mice. Transmitter levels of serotonin, dopamine and norepinephrine (NE) were dysregulated from Postnatal day 7 (P7) to P21 in En2-KO, though NE exhibited the greatest abnormalities. While NE levels were reduced ~35{\%} in forebrain, they were increased 40-75{\%} in hindbrain and cerebellum, and these patterns paralleled changes in locus coeruleus (LC) fiber innervation, respectively. Although En2 promoter was active in Embryonic day 14.5-15.5 LC neurons, expression diminished thereafter and gene deletion did not alter brainstem NE neuron numbers. Significantly, in parallel with reduced NE levels, En2-KO forebrain regions exhibited reduced growth, particularly hippocampus, where P21 dentate gyrus granule neurons were decreased 16{\%}, suggesting abnormal neurogenesis. Indeed, hippocampal neurogenic regions showed increased cell death (+77{\%}) and unexpectedly, increased proliferation. Excess proliferation was restricted to early Sox2/Tbr2 progenitors whereas increased apoptosis occurred in differentiating (Dcx) neuroblasts, accompanied by reduced newborn neuron survival. Abnormal neurogenesis may reflect NE deficits because intra-hippocampal injections of β-adrenergic agonists reversed cell death. These studies suggest that disruption of hindbrain patterning genes can alter monoamine system development and thereby produce forebrain defects that are relevant to human neurodevelopmental disorders.",
author = "Matthieu Genestine and Lulu Lin and Madel Durens and Yan Yan and Yiqin Jiang and Smrithi Prem and Kunal Bailoor and Brian Kelly and Sonsalla, {Patricia K.} and Matteson, {Paul G.} and Silverman, {Jill L} and Jacqueline Crawley and Millonig, {James H.} and Emanuel DiCicco-Bloom",
year = "2015",
month = "6",
day = "5",
doi = "10.1093/hmg/ddv301",
language = "English (US)",
volume = "24",
pages = "5805--5827",
journal = "Human Molecular Genetics",
issn = "0964-6906",
publisher = "Oxford University Press",
number = "20",

}

TY - JOUR

T1 - Engrailed-2 (En2) deletion produces multiple neurodevelopmental defects in monoamine systems, forebrain structures and neurogenesis and behavior

AU - Genestine, Matthieu

AU - Lin, Lulu

AU - Durens, Madel

AU - Yan, Yan

AU - Jiang, Yiqin

AU - Prem, Smrithi

AU - Bailoor, Kunal

AU - Kelly, Brian

AU - Sonsalla, Patricia K.

AU - Matteson, Paul G.

AU - Silverman, Jill L

AU - Crawley, Jacqueline

AU - Millonig, James H.

AU - DiCicco-Bloom, Emanuel

PY - 2015/6/5

Y1 - 2015/6/5

N2 - Many genes involved in brain development have been associated with human neurodevelopmental disorders, but underlying pathophysiological mechanisms remain undefined. Human genetic and mouse behavioral analyses suggest that ENGRAILED-2 (EN2) contributes to neurodevelopmental disorders, especially autism spectrum disorder. In mouse, En2 exhibits dynamic spatiotemporal expression in embryonic mid-hindbrain regions where monoamine neurons emerge. Considering their importance in neuropsychiatric disorders, we characterized monoamine systems in relation to forebrain neurogenesis in En2- knockout (En2-KO) mice. Transmitter levels of serotonin, dopamine and norepinephrine (NE) were dysregulated from Postnatal day 7 (P7) to P21 in En2-KO, though NE exhibited the greatest abnormalities. While NE levels were reduced ~35% in forebrain, they were increased 40-75% in hindbrain and cerebellum, and these patterns paralleled changes in locus coeruleus (LC) fiber innervation, respectively. Although En2 promoter was active in Embryonic day 14.5-15.5 LC neurons, expression diminished thereafter and gene deletion did not alter brainstem NE neuron numbers. Significantly, in parallel with reduced NE levels, En2-KO forebrain regions exhibited reduced growth, particularly hippocampus, where P21 dentate gyrus granule neurons were decreased 16%, suggesting abnormal neurogenesis. Indeed, hippocampal neurogenic regions showed increased cell death (+77%) and unexpectedly, increased proliferation. Excess proliferation was restricted to early Sox2/Tbr2 progenitors whereas increased apoptosis occurred in differentiating (Dcx) neuroblasts, accompanied by reduced newborn neuron survival. Abnormal neurogenesis may reflect NE deficits because intra-hippocampal injections of β-adrenergic agonists reversed cell death. These studies suggest that disruption of hindbrain patterning genes can alter monoamine system development and thereby produce forebrain defects that are relevant to human neurodevelopmental disorders.

AB - Many genes involved in brain development have been associated with human neurodevelopmental disorders, but underlying pathophysiological mechanisms remain undefined. Human genetic and mouse behavioral analyses suggest that ENGRAILED-2 (EN2) contributes to neurodevelopmental disorders, especially autism spectrum disorder. In mouse, En2 exhibits dynamic spatiotemporal expression in embryonic mid-hindbrain regions where monoamine neurons emerge. Considering their importance in neuropsychiatric disorders, we characterized monoamine systems in relation to forebrain neurogenesis in En2- knockout (En2-KO) mice. Transmitter levels of serotonin, dopamine and norepinephrine (NE) were dysregulated from Postnatal day 7 (P7) to P21 in En2-KO, though NE exhibited the greatest abnormalities. While NE levels were reduced ~35% in forebrain, they were increased 40-75% in hindbrain and cerebellum, and these patterns paralleled changes in locus coeruleus (LC) fiber innervation, respectively. Although En2 promoter was active in Embryonic day 14.5-15.5 LC neurons, expression diminished thereafter and gene deletion did not alter brainstem NE neuron numbers. Significantly, in parallel with reduced NE levels, En2-KO forebrain regions exhibited reduced growth, particularly hippocampus, where P21 dentate gyrus granule neurons were decreased 16%, suggesting abnormal neurogenesis. Indeed, hippocampal neurogenic regions showed increased cell death (+77%) and unexpectedly, increased proliferation. Excess proliferation was restricted to early Sox2/Tbr2 progenitors whereas increased apoptosis occurred in differentiating (Dcx) neuroblasts, accompanied by reduced newborn neuron survival. Abnormal neurogenesis may reflect NE deficits because intra-hippocampal injections of β-adrenergic agonists reversed cell death. These studies suggest that disruption of hindbrain patterning genes can alter monoamine system development and thereby produce forebrain defects that are relevant to human neurodevelopmental disorders.

UR - http://www.scopus.com/inward/record.url?scp=84943790821&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84943790821&partnerID=8YFLogxK

U2 - 10.1093/hmg/ddv301

DO - 10.1093/hmg/ddv301

M3 - Article

VL - 24

SP - 5805

EP - 5827

JO - Human Molecular Genetics

JF - Human Molecular Genetics

SN - 0964-6906

IS - 20

ER -