GDNF and GFRα1 Promote Differentiation and Tangential Migration of Cortical GABAergic Neurons

Pozas, Esther; Ibáñez, Carlos F.

doi:10.1016/j.neuron.2005.01.043

Cited by 178 publications

(175 citation statements)

References 63 publications

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“…Recently, ErbB/neuregulin signaling has been implicated in supporting migration through the LGE toward the cerebral cortex (22,23,56). Glial cell line-derived neurotrophic factor signaling via GFR␣1 has a role in the differentiation and migration of cortical GABAergic cells from the MGE (57). Likewise, chemorepellant tissues and factors have been identified that participate in directing these migrations (24,26).…”

Section: Discussionmentioning

confidence: 99%

Dlx Homeobox Genes Promote Cortical Interneuron Migration from the Basal Forebrain by Direct Repression of the Semaphorin Receptor Neuropilin-2

Fonseca

et al. 2007

Journal of Biological Chemistry

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Dlx homeobox genes play an important role in vertebrate forebrain development. Dlx1/Dlx2 null mice die at birth with an abnormal cortical phenotype, including impaired differentiation and migration of GABAergic interneurons to the neocortex. However, the molecular basis for these defects downstream of loss of Dlx1/Dlx2 function is unknown. Neuropilin-2 (NRP-2) is a receptor for Class III semaphorins, which inhibit neuronal migration. Herein, we show that Neuropilin-2 is a specific DLX1 and DLX2 transcriptional target by applying chromatin immunoprecipitation to embryonic forebrain tissues. Both homeobox proteins repress Nrp-2 expression in vitro, confirming the functional significance of DLX binding. Furthermore, the homeodomain of DLX1 and DLX2 is necessary for DNA binding and this binding is essential for Dlx repression of Nrp-2 expression. Of importance, there is up-regulated and aberrant expression of NRP-2 in the forebrains of Dlx1/Dlx2 null mice. This is the first report that DLX1 or DLX2 can function as transcriptional repressors. Our data show that DLX proteins specifically mediate the repression of Neuropilin-2 in the developing forebrain. As well, our results support the hypothesis that down-regulation of Neuropilin-2 expression may facilitate tangential interneuron migration from the basal forebrain.Members of the Dlx homeobox gene family, orthologs of Distal-less in Drosophila melanogaster, are expressed in the developing brain (1, 2), retina (3), craniofacial structures, and limbs (4). Four Dlx genes, Dlx1, Dlx2, Dlx5, and Dlx6, are expressed in overlapping domains in the subcortical telencephalon and diencephalon, including the ventral thalamus and the ganglionic eminences. There are distinct boundaries of Dlx1 and Dlx2 expression at the pallial-subpallial boundary (1). Insights into the functional role of Dlx genes in development have been primarily gained from analysis of the phenotypes of mice with targeted deletions of Dlx1/Dlx2 (5-8), Dlx5 (9), and Dlx5/Dlx6 (10). The single Dlx1 and Dlx2 knockouts have relatively normal forebrain development at birth, which is consistent with functional redundancy between Dlx1 and Dlx2 in this anatomic region (1, 4). However, postnatal Dlx1 mutants show specific differentiation defects in interneuron subclasses (11,12). In the absence of both Dlx1 and Dlx2 function, there is abnormal development of the subventricular zone (SVZ) 2 of the ganglionic eminences. There is an almost complete loss of tangential migration of GABAergic interneurons from the medial ganglionic eminence (MGE) to the neocortex and from the lateral ganglionic eminence (LGE) to the olfactory bulb (5,13) 3 . These migrations comprise the major source of cortical inhibitory interneurons in the murine telencephalon (5, 14, 15). Furthermore, it is evident that there are both Dlx-dependent and Dlxindependent pathways affecting the differentiation and subsequent migration of interneurons to the striatum (6), olfactory bulb (13), and hippocampus (16).Our understanding of Dlx gene function is limit...

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Section: Discussionmentioning

confidence: 99%

Dlx Homeobox Genes Promote Cortical Interneuron Migration from the Basal Forebrain by Direct Repression of the Semaphorin Receptor Neuropilin-2

Fonseca

et al. 2007

Journal of Biological Chemistry

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“…Steps that have been proposed include repulsion from the ganglionic eminences by an as-yet-unidentified factor (Marín et al, 2003), avoidance of the striatum by semaphorinmediated repulsion (Marín et al, 2001), and attraction to the cortex by neuregulins (Flames et al, 2004), GDNF (glial cell linederived neurotrophic factor) (Pozas and Ibanez, 2005), and HGF (hepatocyte growth factor) (Powell et al, 2001), but it has remained unclear why this complex framework is required.…”

Section: Why Have Interneuron Migratory Streams?mentioning

confidence: 99%

Regional Distribution of Cortical Interneurons and Development of Inhibitory Tone Are Regulated by Cxcl12/Cxcr4 Signaling

Li¹,

Adesnik²,

Li³

et al. 2008

J. Neurosci.

180

228

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Interneurons are born in subcortical germinative zones and tangentially migrate in multiple streams above and below the developing cortex, and then, at the appropriate developmental stage, migrate radially into the cortex. The factors that control the formation of and the timing of exit from the streams remain obscure; moreover, the rationale for this complicated developmental plan is unclear. We show that a chemokine, Cxcl12, is an attractant for interneurons during the stage of stream formation and tangential migration. Furthermore, the timing of exit from the migratory streams accompanies loss of responsiveness to Cxcl12 as an attractant. Mice with mutations in Cxcr4 have disorganized migratory streams and deletion of Cxcr4 after the streams have formed precipitates premature entry into the cortical plate. In addition, constitutive deletion of Cxcr4 specifically in interneurons alters the regional distribution of interneurons within the cortex and leads to interneuron laminar positioning defects in the postnatal cortex. To examine the role of interneuron distribution on the development of cortical circuitry, we generated mice with focal defects in interneuron distribution and studied the density of postnatal inhibitory innervation in areas with too many and too few interneurons. Interestingly, alterations in IPSC frequency and amplitude in areas with excess interneurons tend toward normalization of inhibitory tone, but in areas with reduced interneuron density this system fails. Thus, the processes controlling interneuron sorting, migration, regional distribution, and laminar positioning can have significant consequences for the development of cortical circuitry and may have important implications for a range of neurodevelopmental disorders.

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“…This activation decreases NCAM-dependent cell adhesion, illustrating a general principal that an optimal level of cell-substratum contact is needed for motility, with too much or too little impeding it. NCAM also mediates chemo-attraction of olfactory interneuron precursors to GDNF in the rostral migratory stream, but is not required for GDNF/GFRα1-mediated tangential migration of cortical interneurons [29].…”

Section: Ncam Signaling and Post-translational Modificationmentioning

confidence: 99%

L1 and NCAM adhesion molecules as signaling coreceptors in neuronal migration and process outgrowth

Schmid

Maness

2008

Current Opinion in Neurobiology

202

169

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Summary of Recent AdvancesNeural cell adhesion molecules (CAMs) of the immunoglobulin superfamily engage in multiple neuronal interactions that influence cell migration, axonal and dendritic projection, and synaptic targeting. Their downstream signal transduction events specify whether a cell moves or projects axons and dendrites to targets in the brain. Many of the diverse functions of CAMs are brought about through homophilic and heterophilic interactions with other cell surface receptors. An emerging concept is that CAMs act as co-receptors to assist in intracellular signal transduction, and to provide cytoskeletal linkage necessary for cell and growth cone motility. Here we will focus on new discoveries that have revealed novel co-receptor functions for the best understood CAMs -L1, CHL1, and NCAM-important for neuronal migration and axon guidance. We will also discuss how dysregulation of CAMs may also bear on neuropsychiatric disease and cancer.

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GDNF and GFRα1 Promote Differentiation and Tangential Migration of Cortical GABAergic Neurons

Cited by 178 publications

References 63 publications

Dlx Homeobox Genes Promote Cortical Interneuron Migration from the Basal Forebrain by Direct Repression of the Semaphorin Receptor Neuropilin-2

Dlx Homeobox Genes Promote Cortical Interneuron Migration from the Basal Forebrain by Direct Repression of the Semaphorin Receptor Neuropilin-2

Regional Distribution of Cortical Interneurons and Development of Inhibitory Tone Are Regulated by Cxcl12/Cxcr4 Signaling

L1 and NCAM adhesion molecules as signaling coreceptors in neuronal migration and process outgrowth

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