Regionalized Loss of Parvalbumin Interneurons in the Cerebral Cortex of Mice with Deficits in GFRα1 Signaling

Canty, AJ; Dietze, J; Harvey, Michael; Enomoto, Hideki; Milbrandt, Jeffrey; Ibáñez, Carlos F.

doi:10.1523/jneurosci.2658-09.2009

Cited by 60 publications

(77 citation statements)

References 37 publications

(67 reference statements)

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“…Some of the genes expressed in the PV1 nucleus (listed in Table 1) are known to occur in subclasses of GABAergic neurons. These include: Pitx2 (Skidmore et al, 2008;Waite et al, 2011), Scrt (Marin & Nieto, 2006), Scn1a (Ogiwara et al, 2007;Martin et al, 2010), Gfra1 (Pozas & Ibanez, 2005;Canty et al, 2009), Lynx2 (Dessaud et al, 2006 and Tmem163 (Burré et al, 2007). Of the tested genes, only Lynx2, Slc17a6 and Adcyap1 were expressed exclusively in the glutamatergic neurons of the PV1 nucleus.…”

Section: Discussionmentioning

confidence: 99%

Gene expression analysis in the parvalbumin‐immunoreactive PV1 nucleus of the mouse lateral hypothalamus

Girard

Mészàr

Marti

et al. 2011

Eur J of Neuroscience

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A solitary, elongated cluster of parvalbumin-immunoreactive neurons has been previously observed in the rodent ventrolateral hypothalamus. However, the function of this so-called PV1 nucleus is unknown. In this article, we report the results of an unbiased, broad and in-depth molecular characterization of this small, compact group of neurons. The Allen Brain Atlas database of in situ hybridization was screened in order to identify genes expressed in the PV1-nucleus-containing area of the hypothalamus, and those that might be co-expressed with parvalbumin. Although GABA is the principal neurotransmitter in parvalbumin-expressing cells in various other brain areas, we found that PV1 neurons express the vesicular glutamate transporter (VGlut) VGlut2-encoding gene Slc17a6 and are negative for the glutamic acid decarboxylase 1 (GAD1) gene. These cells also express the mRNA for the neuropeptides Adcyap1 and possibly Nxph4, express several types of potassium and sodium channels, are under the control of the neurotransmitter acetylcholine, bear receptors for the glial-derived neurotrophic factor, and produce an extracellular matrix rich in osteopontin. The PV1 nucleus is thus composed of glutamatergic nerve cells, expressing some typical markers of long-axon, projecting neurons (e.g. VGlut2), but also co-expressing genes typical of short-axon GABA neurons (e.g. a variety of potassium channels). Hence, neurons of the PV1 nucleus combine physiological characteristics of interneurons with those of projection neurons.

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Section: Discussionmentioning

confidence: 99%

Gene expression analysis in the parvalbumin‐immunoreactive PV1 nucleus of the mouse lateral hypothalamus

Girard

Mészàr

Marti

et al. 2011

Eur J of Neuroscience

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“…GFR␣1 also associates with the neural cell adhesion molecule, NCAM, to mediate the effects of GDNF independently of RET (4 -6). Some of the activities of GDNF can also be mediated by GFR␣1 in the absence of either RET or NCAM, suggesting alternative mechanisms of transmembrane signaling (7,8). A thorough understanding of the molecular mechanisms by which GDNF functions in different contexts will be essential to elucidating its contribution to nervous system development and exploiting its therapeutic potential.…”

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confidence: 99%

Protein-tyrosine Phosphatase SHP2 Contributes to GDNF Neurotrophic Activity through Direct Binding to Phospho-Tyr687 in the RET Receptor Tyrosine Kinase

Perrinjaquet¹,

Vilar²,

Ibáñez

2010

Journal of Biological Chemistry

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The signaling mechanisms by which neurotrophic receptors regulate neuronal survival and axonal growth are still incompletely understood. In the receptor tyrosine kinase RET, a receptor for GDNF (glial cell line-derived neurotrophic factor), the functions of the majority of tyrosine residues that become phosphorylated are still unknown. Here we have identified the protein-tyrosine phosphatase SHP2 as a novel direct interactor of RET and the first effector known to bind to phosphorylated Tyr 687 in the juxtamembrane region of the receptor. We show that SHP2 is recruited to RET upon ligand binding in a cooperative fashion, such that both interaction with Tyr 687 and association with components of the Tyr 1062 signaling complex are required for stable recruitment of SHP2 to the receptor. SHP2 recruitment contributes to the ability of RET to activate the PI3K/AKT pathway and promote survival and neurite outgrowth in primary neurons. Furthermore, we find that activation of protein kinase A (PKA) by forskolin reduces the recruitment of SHP2 to RET and negatively affects ligand-mediated neurite outgrowth. In agreement with this, mutation of Ser 696 , a known PKA phosphorylation site in RET, enhances SHP2 binding to the receptor and eliminates the effect of forskolin on ligand-induced outgrowth. Together, these findings establish SHP2 as a novel positive regulator of the neurotrophic activities of RET and reveal Tyr 687 as a critical platform for integration of RET and PKA signals. We anticipate that several other phosphotyrosines of unknown function in neuronal receptor tyrosine kinases will also support similar regulatory functions.Neurotrophic factors regulate neuronal survival, morphology, and function and are essential for the development and maintenance of the nervous system. Together with the neurotrophins, glial cell line-derived neurotrophic factor (GDNF) 4 and related family members are among the most important neurotrophic factors in mammals. Because of the potent prosurvival and neuroprotective effects of GDNF on midbrain dopaminergic neurons, much of the initial interest in GDNF was focused on its possible therapeutic effects in Parkinson disease (1, 2). It has more recently been appreciated that GDNF and related factors affect a host of important processes in mature neurons and their precursors and also outside the nervous system. GDNF signals by binding to a receptor complex formed by the ligand-binding subunit GFR␣1 and the signaling subunit RET, a member of the receptor tyrosine kinase (RTK) family (3). GFR␣1 also associates with the neural cell adhesion molecule, NCAM, to mediate the effects of GDNF independently of RET (4 -6). Some of the activities of GDNF can also be mediated by GFR␣1 in the absence of either RET or NCAM, suggesting alternative mechanisms of transmembrane signaling (7,8). A thorough understanding of the molecular mechanisms by which GDNF functions in different contexts will be essential to elucidating its contribution to nervous system development and exploiting its therapeutic poten...

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“…The realization that many of these disorders may have a strong developmental component has directed the focus of current research towards the understanding of those signals and mechanisms that control the development of cortical GABAergic interneurons. GDNF has emerged as an important signaling molecule guiding the differentiation and migration of GABAergic neuron precursors in the MGE (Canty et al, 2009;Pozas and Ibáñez, 2005). In addition to defects in cortical PV interneurons, adult 'cis-only' mice also show abnormal social behavior (Canty et al, 2009), suggesting a possible role for GFR1 in human cognitive disorders.…”

Section: Discussionmentioning

confidence: 99%

“…Neurons isolated from the MGE of mutant mice lacking GFR1 do not respond to GDNF (Pozas and Ibáñez, 2005), indicating the essential requirement of this receptor subunit. Using a mutant mouse line that circumvents the lethality of the null mutation of Gfra1, herein referred to as 'cis-only mice', we have recently found that GFR1 is required for the correct allocation of parvalbumin (PV) expressing interneurons in the cortex (Canty et al, 2009). Cis-only mice displayed a striking loss of PV interneurons in discrete regions of the cerebral cortex (PV holes) interspersed amongst areas of normal density of PV-positive cells (Canty et al, 2009).…”

Section: Introductionmentioning

confidence: 99%

“…Using a mutant mouse line that circumvents the lethality of the null mutation of Gfra1, herein referred to as 'cis-only mice', we have recently found that GFR1 is required for the correct allocation of parvalbumin (PV) expressing interneurons in the cortex (Canty et al, 2009). Cis-only mice displayed a striking loss of PV interneurons in discrete regions of the cerebral cortex (PV holes) interspersed amongst areas of normal density of PV-positive cells (Canty et al, 2009). Since mature PV interneurons do not express GFR1, GFR1 may be downregulated during development in GABAergic MGE precursors and/or function noncell-autonomously.…”

Section: Introductionmentioning

confidence: 99%

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MET signaling in GABAergic neuronal precursors of the medial ganglionic eminence restricts GDNF activity in cells that express GFRα1 and a new transmembrane receptor partner

Perrinjaquet

Sjöstrand

Moliner

et al. 2011

Journal of Cell Science

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GDNF (glial cell line-derived neurotrophic factor) promotes the differentiation and migration of GABAergic neuronal precursors of the medial ganglionic eminence (MGE). These functions are dependent on the GPI-anchored receptor GFRα1, but independent of its two known transmembrane receptor partners RET and NCAM. Here we show that soluble GFRα1 is also able to promote differentiation and migration of GABAergic MGE neurons. These activities require endogenous production of GDNF. Although GDNF responsiveness is abolished in Gfra1−/− neurons, it can be restored upon addition of soluble GFRα1, a result that is only compatible with the existence of a previously unknown transmembrane signaling partner for the GDNF-GFRα1 complex in GABAergic neurons. The roles of two candidate transmembrane receptors previously implicated in GABAergic interneuron development - MET, a receptor for hepatocyte growth factor (HGF), and ErbB4, the neuregulin receptor – were examined. GDNF did not induce the activation of either receptor, nor did inhibition of MET or ErbB4 impair GDNF activity in GABAergic MGE neurons. Unexpectedly, however, inhibition of MET or HGF per se promoted neuronal differentiation and migration and enhanced the activity of GDNF on MGE neurons. These effects were dependent on endogenous GDNF and GFRα1, suggesting that MET signaling negatively regulates GDNF activity in the MGE. In agreement with this, Met mutant MGE neurons showed enhanced responses to GDNF and inhibition of MET or HGF increased Gfra1 mRNA expression in MGE cells. In vivo, expression of MET and GFRα1 overlapped in the MGE, and a loss-of-function mutation in Met increased Gfra1 expression in this region. Together, these observations demonstrate the existence of a novel transmembrane receptor partner for the GDNF–GFRα1 complex and uncover an unexpected interplay between GDNF–GFRα1 and HGF–MET signaling in the early diversification of cortical GABAergic interneuron subtypes.

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Regionalized Loss of Parvalbumin Interneurons in the Cerebral Cortex of Mice with Deficits in GFRα1 Signaling

Cited by 60 publications

References 37 publications

Gene expression analysis in the parvalbumin‐immunoreactive PV1 nucleus of the mouse lateral hypothalamus

Gene expression analysis in the parvalbumin‐immunoreactive PV1 nucleus of the mouse lateral hypothalamus

Protein-tyrosine Phosphatase SHP2 Contributes to GDNF Neurotrophic Activity through Direct Binding to Phospho-Tyr687 in the RET Receptor Tyrosine Kinase

MET signaling in GABAergic neuronal precursors of the medial ganglionic eminence restricts GDNF activity in cells that express GFRα1 and a new transmembrane receptor partner

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