ENGRAILED 2 (EN2) Genetic and Functional Analysis

Choi, Jiyeon; Kamdar, Silky; Rahman, Taslima; Matteson, Paul G.; Millonig, James H.

doi:10.5772/18867

Cited by 4 publications

(4 citation statements)

References 71 publications

(68 reference statements)

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“…Eight association studies have demonstrated significant association for EN2 with autism spectrum disorder (ASD) (reviewed in Choi et al ), supporting the interpretation that EN2 is an autism susceptibility gene. Autism spectrum disorders affect approximately 1% of the population (Centers for Disease Control ).…”

mentioning

confidence: 92%

Chronic desipramine treatment rescues depression‐related, social and cognitive deficits in Engrailed‐2 knockout mice

Brielmaier

Senerth

Silverman

et al. 2014

Genes Brain and Behavior

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Engrailed-2 (En2) is a homeobox transcription factor that regulates neurodevelopmental processes including neuronal connectivity and elaboration of monoaminergic neurons in the ventral hindbrain. We previously reported abnormalities in brain noradrenergic concentrations in En2 null mutant mice that were accompanied by increased immobility in the forced swim test, relevant to depression. An EN2 genetic polymorphism has been associated with autism spectrum disorders (ASD), and mice with a deletion in En2 display social abnormalities and cognitive deficits that may be relevant to multiple neuropsychiatric conditions. The present study evaluated the ability of chronic treatment with desipramine (DMI), a selective norepinephrine reuptake inhibitor and classical antidepressant, to reverse behavioral abnormalities in En2 −/− mice. DMI treatment significantly reduced immobility in the tail suspension and forced swim tests, restored sociability in the three-chambered social approach task, and reversed impairments in contextual fear conditioning in En2 −/− mice. Our findings indicate that modulation of brain noradrenergic systems rescues the depression-related phenotype in En2 −/− mice and suggest new roles for norepinephrine in the pathophysiology of the social and cognitive deficits seen in neuropsychiatric disorders such as autism or schizophrenia.

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mentioning

confidence: 92%

Chronic desipramine treatment rescues depression‐related, social and cognitive deficits in Engrailed‐2 knockout mice

Brielmaier

Senerth

Silverman

et al. 2014

Genes Brain and Behavior

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“…Moreover, human EN2 has been associated with ASD in a number of studies. Two intronic EN2 polymorphisms have been genetically associated with ASD and have been shown in independent cohorts and populations to be overtransmitted to autistic offspring from heterozygous parents (reviewed in Brune et al, 2008;Choi et al, 2011;Kuan et al, 2015;Sen et al, 2010;Wang et al, 2008). Additionally, rare mutations in EN2 have been reported in ASD patients (Carratala-Marco et al, 2018;Hnoonual et al, 2016), and dysregulation of EN2 expression has been observed in two independent studies of postmortem cerebellar tissue in ASD (Choi et al, 2014;James et al, 2013).…”

Section: En2 and Neurodevelopmental Disordersmentioning

confidence: 99%

“…Abnormalities in genes that regulate early brain development are frequently risk factors for neurodevelopmental disorders (reviewed in Brune et al, 2008;Choi et al, 2011;Kuan et al, 2015;Parenti et al, 2020;Sen et al, 2010;Wang et al, 2008). The function of the homeodomain transcription factor engrailed-2 (En2) in patterning the cerebellum and mid-hindbrain has been studied extensively; however, its roles in the forebrain are only beginning to be understood.…”

Section: Introductionmentioning

confidence: 99%

“…Abnormal hippocampal neurogenesis has been implicated in numerous neuropsychiatric disorders including autism spectrum disorder (ASD) (Aimone et al, 2014;Kang et al, 2016;Varghese et al, 2017;Wegiel et al, 2010). Moreover, genetic and postmortem studies have also implicated human EN2 in ASD etiology (Brune et al, 2008;Choi et al, 2011Choi et al, , 2014James et al, 2013;Wang et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

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Engrailed‐2 is a cell autonomous regulator of neurogenesis in cultured hippocampal neural stem cells

Durens

Soliman

Millonig

et al. 2021

Developmental Neurobiology

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Abnormalities in genes that regulate early brain development are known risk factors for neurodevelopmental disorders. Engrailed-2 (En2) is a homeodomain transcription factor with established roles in cerebellar patterning. En2 is highly expressed in the developing mid-hindbrain region, and En2 knockout (KO) mice exhibit major deficits in mid-hindbrain structures. However, En2 is also expressed in forebrain regions including the hippocampus, but its function is unknown. Previous studies have shown that the hippocampus of En2-KO mice exhibits reductions in its volume and cell numbers due to aberrant neurogenesis. Aberrant neurogenesis is due, in part, to noncell autonomous effects, specifically, reductions of innervating norepinephrine fibers from the locus coeruleus. In this study, we investigate possible cell autonomous roles of En2 in hippocampal neurogenesis. We examine proliferation, survival, and differentiation using cultures of hippocampal neurospheres of P7 wild-type (WT) and En2-KO hippocampal neural progenitor cells (NPCs). At 7 days, En2-KO neurospheres were larger on average than WT spheres and exhibited 2.5fold greater proliferation and 2-fold increase in apoptotic cells, similar to in vivo KO phenotype. Further, En2-KO cultures exhibited 40% less cells with neurite projections, suggesting decreased differentiation. Lastly, reestablishing En2 expression in En2-KO NPCs rescued excess proliferation. These results indicate that En2 functions in hippocampal NPCs by inhibiting proliferation and promoting survival and differentiation in a cell autonomous manner. More broadly, this study suggests that En2 impacts brain structure and function in diverse regions outside of the mid-hindbrain. K E Y W O R D Sanimal models, engrailed-2, hippocampal neurogenesis, neural progenitor/stem cell cultures, neurodevelopmental disorders Significance statementAlthough En2 function in mid-hindbrain development is widely characterized, consistent expression in forebrain regions has been reported, but its function(s) remains unknown. In this study, we found that relatively low levels of En2 in the hippocampus contribute to hippocampal neurogenesis in a cell-autonomous manner, by influencing proliferation, apoptosis, and differentiation of hippocampal NPCs. In conjunction with our previous results, these data indicate that En2 regulates hippocampal neurogenesis in both a cell autonomous and non-cell autonomous manner. In turn, | 725

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Tactile sensory processing deficits in genetic mouse models of autism spectrum disorder

Falcão,

Monteiro,

Jacinto

2024

Journal of Neurochemistry

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Altered sensory processing is a common feature in autism spectrum disorder (ASD), as recognized in the Diagnostic and Statistical Manual of Mental Disorders (DSM‐5). Although altered responses to tactile stimuli are observed in over 60% of individuals with ASD, the neurobiological basis of this phenomenon is poorly understood. ASD has a strong genetic component and genetic mouse models can provide valuable insights into the mechanisms underlying tactile abnormalities in ASD. This review critically addresses recent findings regarding tactile processing deficits found in mouse models of ASD, with a focus on behavioral, anatomical, and functional alterations. Particular attention was given to cellular and circuit‐level functional alterations, both in the peripheral and central nervous systems, with the objective of highlighting possible convergence mechanisms across models. By elucidating the impact of mutations in ASD candidate genes on somatosensory circuits and correlating them with behavioral phenotypes, this review significantly advances our understanding of tactile deficits in ASD. Such insights not only broaden our comprehension but also pave the way for future therapeutic interventions.image

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ENGRAILED 2 (EN2) Genetic and Functional Analysis

Cited by 4 publications

References 71 publications

Chronic desipramine treatment rescues depression‐related, social and cognitive deficits in Engrailed‐2 knockout mice

Chronic desipramine treatment rescues depression‐related, social and cognitive deficits in Engrailed‐2 knockout mice

Engrailed‐2 is a cell autonomous regulator of neurogenesis in cultured hippocampal neural stem cells

Tactile sensory processing deficits in genetic mouse models of autism spectrum disorder

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