C3G regulates cortical neuron migration, preplate splitting and radial glial cell attachment

Voss, Anne K.; Britto, Joanne M.; Dixon, Mathew P.; Sheikh, Bilal N.; Collin, Caitlin; Tan, Seong‐Seng; Thomas, Tim

doi:10.1242/dev.016725

Cited by 80 publications

(78 citation statements)

References 56 publications

(88 reference statements)

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“…RapGef1-deficient mouse embryos exhibit a cortical neuron migration defect resulting in a failure to split the preplate into marginal zone and subplate and a failure to form a cortical plate (27). Quantitative RT-PCR of RAPGEF1 in CLN3-depleted cells confirmed the significant increase in mRNA expression in CLN3 patients with rapid progression.…”

Section: Identification Of Potential Modifier Genes For Cln3 Diseasementioning

confidence: 74%

Analysis of Potential Biomarkers and Modifier Genes Affecting the Clinical Course of CLN3 Disease

Lebrun

Moll-Khosrawi

Pohl

et al. 2011

Mol Med

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Mutations in the CLN3 gene lead to juvenile neuronal ceroid lipofuscinosis, a pediatric neurodegenerative disorder characterized by visual loss, epilepsy and psychomotor deterioration. Although most CLN3 patients carry the same 1-kb deletion in the CLN3 gene, their disease phenotype can be variable. The aims of this study were to (i) study the clinical phenotype in CLN3 patients with identical genotype, (ii) identify genes that are dysregulated in CLN3 disease regardless of the clinical course that could be useful as biomarkers, and (iii) find modifier genes that affect the progression rate of the disease. A total of 25 CLN3 patients homozygous for the 1-kb deletion were classified into groups with rapid, average or slow disease progression using an established clinical scoring system. Genome-wide expression profiling was performed in eight CLN3 patients with different disease progression and matched controls. The study showed high phenotype variability in CLN3 patients. Five genes were dysregulated in all CLN3 patients and present candidate biomarkers of the disease. Of those, dual specificity phosphatase 2 (DUSP2 ) was also validated in acutely CLN3-depleted cell models and in CbCln3Δex7/8 cerebellar precursor cells. A total of 13 genes were upregulated in patients with rapid disease progression and downregulated in patients with slow disease progression; one gene showed dysregulation in the opposite way. Among these potential modifier genes, guanine nucleotide exchange factor 1 for small GTPases of the Ras family (RAPGEF1) and transcription factor Spi-B (SPIB) were validated in an acutely CLN3-depleted cell model. These findings indicate that differential perturbations of distinct signaling pathways might alter disease progression and provide insight into the molecular alterations underlying neuronal dysfunction in CLN3 disease and neurodegeneration in general.

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Section: Identification Of Potential Modifier Genes For Cln3 Diseasementioning

confidence: 74%

Analysis of Potential Biomarkers and Modifier Genes Affecting the Clinical Course of CLN3 Disease

Lebrun

Moll-Khosrawi

Pohl

et al. 2011

Mol Med

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“…Other proteins such as Nck␤ and Lis1 may also be present and could be phosphorylated by the associated SFK. Which of the bound proteins is required for proper migration remains to be discovered, although a recent study of C3G mutant mice showed that C3G is needed for the normal migration of cortical neurons in vivo (39), suggesting that C3G phosphorylation may be crucial.…”

Section: Resultsmentioning

confidence: 99%

Dual Functions of Dab1 during Brain Development

Cooper

2009

Molecular and Cellular Biology

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“…Although additional experiments are required to identify these cues, they might include extracellular matrix (ECM) components. The SP is rich in ECM components (Henke-Fahle et al, 1996;Voss et al, 2008), which can modulate axonal responses to guidance cues (Höpker et al, 1999;Nguyen-Ba-Charvet et al, 2001;Kantor et al, 2004).…”

Section: Npn-2 Controls Mpfc Innervation Through the External Capsulementioning

confidence: 99%

Semaphorin 3F Is a Bifunctional Guidance Cue for Dopaminergic Axons and Controls Their Fasciculation, Channeling, Rostral Growth, and Intracortical Targeting

Kolk¹,

Gunput²,

Tran³

et al. 2009

J. Neurosci.

102

138

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Dopaminergic neurons in the mesodiencephalon (mdDA neurons) make precise synaptic connections with targets in the forebrain via the mesostriatal, mesolimbic, and mesoprefrontal pathways. Because of the functional importance of these remarkably complex ascending axon pathways and their implication in human disease, the mechanisms underlying the development of these connections are of considerable interest. Despite extensive in vitro studies, the molecular determinants that ensure the perfect formation of these pathways in vivo remain mostly unknown. Here, we determine the embryonic origin and ontogeny of the mouse mesoprefrontal pathway and use these data to reveal an unexpected requirement for semaphorin 3F (Sema3F) and its receptor neuropilin-2 (Npn-2) during mdDA pathway development using tissue culture approaches and analysis of sema3F Ϫ / Ϫ , npn-2 Ϫ / Ϫ , and npn-2 Ϫ / Ϫ ;TH-Cre mice. We show that Sema3F is a bifunctional guidance cue for mdDA axons, some of which have the remarkable ability to regulate their responsiveness to Sema3F as they develop. During early developmental stages, Sema3F chemorepulsion controls previously uncharacterized aspects of mdDA pathway development through both Npn-2-dependent (axon fasciculation and channeling) and Npn-2-independent (rostral growth) mechanisms. Later on, chemoattraction mediated by Sema3F and Npn-2 is required to orient mdDA axon projections in the cortical plate of the medial prefrontal cortex. This latter finding demonstrates that regulation of axon orientation in the target field occurs by chemoattractive mechanisms, and this is likely to also apply to other neural systems. In all, this study provides a framework for additional dissection of the molecular basis of mdDA pathway development and disease.

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C3G regulates cortical neuron migration, preplate splitting and radial glial cell attachment

Cited by 80 publications

References 56 publications

Analysis of Potential Biomarkers and Modifier Genes Affecting the Clinical Course of CLN3 Disease

Analysis of Potential Biomarkers and Modifier Genes Affecting the Clinical Course of CLN3 Disease

Dual Functions of Dab1 during Brain Development

Semaphorin 3F Is a Bifunctional Guidance Cue for Dopaminergic Axons and Controls Their Fasciculation, Channeling, Rostral Growth, and Intracortical Targeting

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