Hepatocyte Growth Factor/Scatter Factor Is a Motogen for Interneurons Migrating from the Ventral to Dorsal Telencephalon

Powell, Elizabeth M.; Mars, Wendy M.; Levitt, Pat

doi:10.1016/s0896-6273(01)00264-1

Cited by 301 publications

(299 citation statements)

References 48 publications

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“…Several of the methylation CpG sites are next to AT-runs that are high affinity sites for MeCP2. 33 In conclusion, epigenetic defects in autism samples may lead to the overlapping phenotypes with RTT and AS.…”

Section: Role Of Phosphorylation In Regulation Of Mecp2 Functionmentioning

confidence: 92%

Epigenetics and Neural Developmental Disorders

Zhao

Pak²,

Smrt³

et al. 2007

Epigenetics

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Neural developmental disorders, such as autism, Rett Syndrome, Fragile X syndrome, and Angelman syndrome manifest during early postnatal neural development. Although the genes responsible for some of these disorders have been identified, how the mutations of these genes affect neural development is currently unclear. Emerging evidence suggest that these disorders share common underlying defects in neuronal morphology, synaptic connectivity and brain plasticity. In particular, alterations in dendritic branching and spine morphology play a central role in the pathophysiology of most mental retardation disorders, suggesting that common pathways regulating neuronal function may be affected. Epigenetic modulations, mediated by DNA methylation, RNA-associated silencing, and histone modification, can serve as an intermediate process that imprints dynamic environmental experiences on the "fixed" genome, resulting in stable alterations in phenotypes. Disturbance in epigenetic regulations can lead to inappropriate expression or silencing of genes, causing an array of multi-system disorders and neoplasias. Rett syndrome, the most common form of mental retardation in young girls, is due to l mutation of MECP2, encoding a methylated DNA binding protein that translates DNA methylation into gene repression. Angelman syndrome is due to faulty genomic imprinting or maternal mutations in UBE3A. Fragile X Syndrome, in most cases, results from the hypermethylation of FMR1 promoter, hence the loss of expression of functional FMRP protein. Autism, with its complex etiology, may have strong epigenetic link. Together, these observations strongly suggest that epigenetic mechanisms may play a critical role in brain development and etiology of related disorders. This report summarizes the scientific discussions and major conclusions from a recent conference that aimed to gain insight into the common molecular pathways affected among these disorders and discover potential therapeutic targets that have been missed by looking at one disorder at a time.

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Section: Role Of Phosphorylation In Regulation Of Mecp2 Functionmentioning

confidence: 92%

Epigenetics and Neural Developmental Disorders

Zhao

Pak²,

Smrt³

et al. 2007

Epigenetics

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“…Recent studies by our group and others revealed that MET also contributes to development of the cerebral cortex (25,26) and cerebellum (27), both of which exhibit developmental disruptions in autism (28,29). Hypomorphic MET͞HGF signaling in the cerebral cortex results in abnormal interneuron migration from the ganglionic eminence and reduced interneurons in the frontal and parietal regions of cortex (25,26). Hypomorphic MET͞HGF signaling in the cerebellum causes decreased proliferation of granule cells and a concomitant reduction in the size of the cerebellum, particularly in the vermis (27).…”

mentioning

confidence: 88%

“…MET signaling contributes to immune function (20)(21)(22) and gastrointestinal repair (18,23,24). Recent studies by our group and others revealed that MET also contributes to development of the cerebral cortex (25,26) and cerebellum (27), both of which exhibit developmental disruptions in autism (28,29). Hypomorphic MET͞HGF signaling in the cerebral cortex results in abnormal interneuron migration from the ganglionic eminence and reduced interneurons in the frontal and parietal regions of cortex (25,26).…”

mentioning

confidence: 99%

A genetic variant that disrupts MET transcription is associated with autism

Campbell¹,

Sutcliffe

Ebert³

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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391

352

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There is strong evidence for a genetic predisposition to autism and an intense interest in discovering heritable risk factors that disrupt gene function. Based on neurobiological findings and location within a chromosome 7q31 autism candidate gene region, we analyzed the gene encoding the pleiotropic MET receptor tyrosine kinase in a family based study of autism including 1,231 cases. MET signaling participates in neocortical and cerebellar growth and maturation, immune function, and gastrointestinal repair, consistent with reported medical complications in some children with autism. Here, we show genetic association (P ‫؍‬ 0.0005) of a common C allele in the promoter region of the MET gene in 204 autism families. The allelic association at this MET variant was confirmed in a replication sample of 539 autism families (P ‫؍‬ 0.001) and in the combined sample (P ‫؍‬ 0.000005). Multiplex families, in which more than one child has autism, exhibited the strongest allelic association (P ‫؍‬ 0.000007). In case-control analyses, the autism diagnosis relative risk was 2.27 (95% confidence interval: 1.41-3.65; P ‫؍‬ 0.0006) for the CC genotype and 1.67 (95% confidence interval: 1.11-2.49; P ‫؍‬ 0.012) for the CG genotype compared with the GG genotype. Functional assays showed that the C allele results in a 2-fold decrease in MET promoter activity and altered binding of specific transcription factor complexes. These data implicate reduced MET gene expression in autism susceptibility, providing evidence of a previously undescribed pathophysiological basis for this behaviorally and medically complex disorder.autism spectrum disorder ͉ association ͉ candidate gene ͉ hepatocyte growth factor ͉ hepatocyte growth factor receptor

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“…Hepatocyte growth factor (HGF) activates the c-Met receptor, leading to the formation of matrix metalloproteinases (15) that digest collagen and other extracellular components of the interstitium, facilitating cell migration and homing in the brain (16) and other organs. Importantly, HGF enhances vessel growth and favors cell-extracellular matrix interaction, which may be critical during myocardial regeneration after infarction.…”

mentioning

confidence: 99%

Stem cells in the dog heart are self-renewing, clonogenic, and multipotent and regenerate infarcted myocardium, improving cardiac function

Linke

Müller

Nurzynska

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

527

386

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The purpose of this study was to determine whether the heart in large mammals contains cardiac progenitor cells that regulate organ homeostasis and regenerate dead myocardium after infarction. We report that the dog heart possesses a cardiac stem cell pool characterized by undifferentiated cells that are self-renewing, clonogenic, and multipotent. These clonogenic cells and early committed progeny possess a hepatocyte growth factor (HGF)-cMet and an insulin-like growth factor 1 (IGF-1)-IGF-1 receptor system that can be activated to induce their migration, proliferation, and survival. Therefore, myocardial infarction was induced in chronically instrumented dogs implanted with sonomicrometric crystals in the region of the left ventricular wall supplied by the occluded left anterior descending coronary artery. After infarction, HGF and IGF-1 were injected intramyocardially to stimulate resident cardiac progenitor cells. This intervention led to the formation of myocytes and coronary vessels within the infarct. Newly generated myocytes expressed nuclear and cytoplasmic proteins specific of cardiomyocytes: MEF2C was detected in the nucleus, whereas ␣-sarcomeric actin, cardiac myosin heavy chain, troponin I, and ␣-actinin were identified in the cytoplasm. Connexin 43 and N-cadherin were also present. Myocardial reconstitution resulted in a marked recovery of contractile performance of the infarcted heart. In conclusion, the activation of resident primitive cells in the damaged dog heart can promote a significant restoration of dead tissue, which is paralleled by a progressive improvement in cardiac function. These results suggest that strategies capable of activating the growth reserve of the myocardium may be important in cardiac repair after ischemic injury.cardiac stem cells ͉ myocardial infarction ͉ myocardial regeneration

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Hepatocyte Growth Factor/Scatter Factor Is a Motogen for Interneurons Migrating from the Ventral to Dorsal Telencephalon

Cited by 301 publications

References 48 publications

Epigenetics and Neural Developmental Disorders

Epigenetics and Neural Developmental Disorders

A genetic variant that disrupts MET transcription is associated with autism

Stem cells in the dog heart are self-renewing, clonogenic, and multipotent and regenerate infarcted myocardium, improving cardiac function

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