Autism Associated Gene, ENGRAILED2, and Flanking Gene Levels Are Altered in Post-Mortem Cerebellum

Choi, Jiyeon; Ababon, Myka R.; Soliman, Mai; Lin, Yong; Brzustowicz, Linda M.; Matteson, Paul G.; Millonig, James H.

doi:10.1371/journal.pone.0087208

Cited by 33 publications

(28 citation statements)

References 54 publications

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“…Furthermore, our recent studies indicate that in human cerebellum, the disease-associated allele produces increased EN2 expression [100]. If the En2 activity defined here in rodent studies is relevant to primates, how then would altered EN2 expression be expected to affect humans?…”

Section: Discussionmentioning

confidence: 98%

Engrailed2 modulates cerebellar granule neuron precursor proliferation, differentiation and insulin-like growth factor 1 signaling during postnatal development

et al. 2014

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BackgroundThe homeobox transcription factor Engrailed2 (En2) has been studied extensively in neurodevelopment, particularly in the midbrain/hindbrain region and cerebellum, where it exhibits dynamic patterns of expression and regulates cell patterning and morphogenesis. Because of its roles in regulating cerebellar development and evidence of cerebellar pathology in autism spectrum disorder (ASD), we previously examined an ENGRAILED2 association and found evidence to support EN2 as a susceptibility gene, a finding replicated by several other investigators. However, its functions at the cell biological level remain undefined. In the mouse, En2 gene is expressed in granule neuron precursors (GNPs) just as they exit the cell cycle and begin to differentiate, raising the possibility that En2 may modulate these developmental processes.MethodsTo define En2 functions, we examined proliferation, differentiation and signaling pathway activation in En2 knockout (KO) and wild-type (WT) GNPs in response to a variety of extracellular growth factors and following En2 cDNA overexpression in cell culture. In vivo analyses of cerebellar GNP proliferation as well as responses to insulin-like growth factor-1 (IGF1) treatment were also conducted.ResultsProliferation markers were increased in KO GNPs in vivo and in 24-h cultures, suggesting En2 normally serves to promote cell cycle exit. Significantly, IGF1 stimulated greater DNA synthesis in KO than WT cells in culture, a finding associated with markedly increased phospho-S6 kinase activation. Similarly, there was three-fold greater DNA synthesis in the KO cerebellum in response to IGF1 in vivo. On the other hand, KO GNPs exhibited reduced neurite outgrowth and differentiation. Conversely, En2 overexpression increased cell cycle exit and promoted neuronal differentiation.ConclusionsIn aggregate, our observations suggest that the ASD-associated gene En2 promotes GNP cell cycle exit and differentiation, and modulates IGF1 activity during postnatal cerebellar development. Thus, genetic/epigenetic alterations of EN2 expression may impact proliferation, differentiation and IGF1 signaling as possible mechanisms that may contribute to ASD pathogenesis.

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Section: Discussionmentioning

confidence: 98%

Engrailed2 modulates cerebellar granule neuron precursor proliferation, differentiation and insulin-like growth factor 1 signaling during postnatal development

et al. 2014

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“…This may explain clinical observations suggesting that IR‐mediated processes are involved in the pathogenesis of neurodevelopmental conditions and cancer . In particular, genetic studies accompanied by additional assays revealed a link between deficiencies in the IR‐mediated signaling and autistic‐like spectrum disorders that particularly concern insulin‐induced gene‐1 (INSIG1) . In addition, genetic mutations of gene encoding a receptor of IGF‐1 were shown to be associated with developmental delay …”

Section: Insulin Receptor–mediated Signaling and Cns Pathologiesmentioning

confidence: 98%

Insulin receptor in the brain: Mechanisms of activation and the role in the CNS pathology and treatment

et al. 2018

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While the insulin receptor (IR) was found in the CNS decades ago, the brain was long considered to be an insulin-insensitive organ. This view is currently revisited, given emerging evidence of critical roles of IR-mediated signaling in development, neuroprotection, metabolism, and plasticity in the brain. These diverse cellular and physiological IR activities are distinct from metabolic IR functions in peripheral tissues, thus highlighting region specificity of IR properties. This particularly concerns the fact that two IR isoforms, A and B, are predominantly expressed in either the brain or peripheral tissues, respectively, and neurons express exclusively IR-A. Intriguingly, in comparison with IR-B, IR-A displays high binding affinity and is also activated by low concentrations of insulin-like growth factor-2 (IGF-2), a regulator of neuronal plasticity, whose dysregulation is associated with neuropathologic processes. Deficiencies in IR activation, insulin availability, and downstream IR-related mechanisms may result in aberrant IR-mediated functions and, subsequently, a broad range of brain disorders, including neurodevelopmental syndromes, neoplasms, neurodegenerative conditions, and depression. Here, we discuss findings on the brain-specific features of IR-mediated signaling with focus on mechanisms of primary receptor activation and their roles in the neuropathology. We aimed to uncover the remaining gaps in current knowledge on IR physiology and highlight new therapies targeting IR, such as IR sensitizers.

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“…En2 cerebellar expression is high, whereas disruption in these expression levels has been found in studies examining postmortem ASD subject brain samples [37]. To better understand En2 function, transgenic mice were developed and found to have abnormal development of the cerebellum.…”

Section: Engrailedmentioning

confidence: 99%

Autism and cerebellar dysfunction: Evidence from animal models

Tsai

2016

Seminars in Fetal and Neonatal Medicine

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Autism Associated Gene, ENGRAILED2, and Flanking Gene Levels Are Altered in Post-Mortem Cerebellum

Cited by 33 publications

References 54 publications

Engrailed2 modulates cerebellar granule neuron precursor proliferation, differentiation and insulin-like growth factor 1 signaling during postnatal development

Engrailed2 modulates cerebellar granule neuron precursor proliferation, differentiation and insulin-like growth factor 1 signaling during postnatal development

Insulin receptor in the brain: Mechanisms of activation and the role in the CNS pathology and treatment

Autism and cerebellar dysfunction: Evidence from animal models

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