Gene Targeting Reveals a Critical Role for Neurturin in the Development and Maintenance of Enteric, Sensory, and Parasympathetic Neurons

Heuckeroth, Robert O.; Enomoto, Hideki; Grider, John R.; Golden, Judith P.; Hanke, Julie A; Jackman, Alana; Molliver, Derek C.; Bardgett, Mark E.; Snider, William D.; Johnson, Eugene M.; Milbrandt, Jeffrey

doi:10.1016/s0896-6273(00)81087-9

Cited by 298 publications

(243 citation statements)

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“…2B,D). These reductions are reminiscent of ENS deficits that appear in GDNF (decreased neuron number) or NRTN (decreased fiber density) deficient mice, indicating that Ret DN/+ mice have a combination of deficits resulting from an overall reduction in GFL-mediated Ret activation (Gianino et al, 2003;Heuckeroth et al, 1999;Rossi et al, 1999).…”

Section: Long-segment Distal Intestinal Aganglionosis In Ret Dn/+ Micementioning

confidence: 97%

“…3A). While GDNFmediated Ret activation is crucial for formation of SPG neurons, NRTN and GFRα2 are necessary for SPG trophic maintenance and innervation of the intraorbital harderian glands (Heuckeroth et al, 1999;Rossi et al, 1999). The postnatal survival of Ret DN/+ mice allowed us to determine whether the SPG neurons that were generated are affected by the decreased Ret activity.…”

Section: Long-segment Distal Intestinal Aganglionosis In Ret Dn/+ Micementioning

confidence: 99%

“…

spermatogenesis has been suggested following the analysis of mice that overexpress GDNF in the testes (Gianino et al, 2003;Heuckeroth et al, 1999;Meng et al, 2000;Rossi et al, 1999). Unfortunately, the perinatal lethality of Ret-null animals has made it impossible to study the postnatal roles of Ret, and to develop animal models that mimic Ret-related human diseases.

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confidence: 99%

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Mice expressing a dominant-negative Ret mutation phenocopy human Hirschsprung disease and delineate a direct role of Ret in spermatogenesis

et al. 2004

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spermatogenesis has been suggested following the analysis of mice that overexpress GDNF in the testes (Gianino et al., 2003;Heuckeroth et al., 1999;Meng et al., 2000;Rossi et al., 1999). Unfortunately, the perinatal lethality of Ret-null animals has made it impossible to study the postnatal roles of Ret, and to develop animal models that mimic Ret-related human diseases. This has hindered the molecular understanding of these diseases, and the subsequent development and testing of novel treatment strategies.Ret signaling is mediated by the binding of the GFLs [GDNF, neurturin (NRTN), artemin (ARTN) and persephin (PSPN)] with their cognate glycophosphatidylinositol (GPI)-anchored GFRα1-4 co-receptor, and their subsequent interaction with the Ret extracellular domain (Baloh et al., 2000). These interactions result in functional GFL-GFRα-Ret complexes and the autophosphorylation of key Ret tyrosine residues that harbor consensus sequences for adaptor proteins. Recruitment of these adaptor proteins to phosphorylated Ret tyrosine residues activates multiple signaling pathways, including the mitogen-activated protein kinase (MAPK) and the phosphoinositide 3-kinase (PI3K)-AKT pathways that regulate cell survival, proliferation, migration and axonalThe Ret receptor tyrosine kinase mediates physiological signals of glial cell line-derived neurotrophic factor (GDNF) family ligands (GFLs) and is essential for postnatal survival in mice. It is implicated in a number of human diseases and developmental abnormalities. Here, we describe our analyses of mice expressing a Ret mutant (RetDN) with diminished kinase activity that inhibits wildtype Ret activity, including its activation of AKT. All Ret DN/+ mice died by 1 month of age and had distal intestinal aganglionosis reminiscent of Hirschsprung disease (HSCR) in humans. The Ret DN/+ proximal small intestine also had severe hypoganglionosis and reduction in nerve fiber density, suggesting a potential mechanism for the continued gastric dysmotility in postsurgical HSCR patients. Unlike Ret-null mice, which have abnormalities in the parasympathetic and sympathetic nervous systems, the Ret DN/+ mice only had defects in the parasympathetic nervous system. A small proportion of Ret DN/+ mice had renal agenesis, and the remainder had hypoplastic kidneys and developed tubulocystic abnormalities postnatally. Postnatal analyses of the testes revealed a decreased number of germ cells, degenerating seminiferous tubules, maturation arrest and apoptosis, indicating a crucial role for Ret in early spermatogenesis.

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Section: Long-segment Distal Intestinal Aganglionosis In Ret Dn/+ Micementioning

confidence: 97%

Section: Long-segment Distal Intestinal Aganglionosis In Ret Dn/+ Micementioning

confidence: 99%

“…

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Mice expressing a dominant-negative Ret mutation phenocopy human Hirschsprung disease and delineate a direct role of Ret in spermatogenesis

et al. 2004

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“…Development of many PNS ganglia is regulated by GDNF and NTN (Durbec et al, 1996;Golden et al, 1998;Heuckeroth et al, 1999;Enomoto et al, 2000). Our present expression and functional data indicates that ART also plays a critical role in differentiation and maintenance of these structures.…”

Section: Recombinant Art Does Not Relieve Neuropathic Painmentioning

confidence: 99%

The Candidate Neuroprotective Agent Artemin Induces Autonomic Neural Dysplasia without Preventing Peripheral Nerve Dysfunction

et al. 2004

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Artemin (ART) signals through the GFRα-3/RET receptor complex to support sympathetic neuron development. Here we show that ART also influences autonomic elements in adrenal medulla and enteric and pelvic ganglia. Transgenic mice over-expressing Art throughout development exhibited systemic autonomic neural lesions including fusion of adrenal medullae with adjacent paraganglia, adrenal medullary dysplasia, and marked enlargement of sympathetic (superior cervical and sympathetic chain ganglia) and parasympathetic (enteric, pelvic) ganglia. Changes began by gestational day 12.5 and formed progressively larger masses during adulthood. Art supplementation in wild type adult mice by administering recombinant protein or an Art-bearing retroviral vector resulted in hyperplasia or neuronal metaplasia at the adrenal corticomedullary junction. Expression data revealed that Gfrα-3 is expressed during development in the adrenal medulla, sensory and autonomic ganglia and their projections, while Art is found in contiguous mesenchymal domains (especially skeleton) and in certain nerves. Intrathecal Art therapy did not reduce hypalgesia in rats following nerve ligation. These data (1) confirm that ART acts as a differentiation factor for autonomic (chiefly sympathoadrenal but also parasympathetic) neurons, (2) suggest a role for ART overexpression in the genesis of pheochromocytomas and paragangliomas, and (3) indicate that ART is not a suitable therapy for peripheral neuropathy.

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“…In crosssection, this plexus presents a simple centrifugal ring structure, but when viewed superficially, it is organized as an extensive mesh-like tubular arborization encasing the gut wall. Axonal arborization along the gut smooth muscles is controlled by overlapping and sequential actions of GDNF and Neuturin, a GDNF family member acting mainly postnatally (3,4). Recently, the planar polarity pathway has also been implicated in enteric connectivity (5).…”

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Gas1 is a receptor for sonic hedgehog to repel enteric axons

Jin

Martinelli

Zheng

et al. 2014

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

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The myenteric plexus of the enteric nervous system controls the movement of smooth muscles in the gastrointestinal system. They extend their axons between two peripheral smooth muscle layers to form a tubular meshwork arborizing the gut wall. How a tubular axonal meshwork becomes established without invading centrally toward the gut epithelium has not been addressed. We provide evidence here that sonic hedgehog (Shh) secreted from the gut epithelium prevents central projections of enteric axons, thereby forcing their peripheral tubular distribution. Exclusion of enteric central projections by Shh requires its binding partner growth arrest specific gene 1 (Gas1) and its signaling component smoothened (Smo) in enteric neurons. Using enteric neurons differentiated from neurospheres in vitro, we show that enteric axon growth is not inhibited by Shh. Rather, when Shh is presented as a point source, enteric axons turn away from it in a Gas1-dependent manner. Of the Gαi proteins that can couple with Smo, G protein α Z (Gnaz) is found in enteric axons. Knockdown and dominant negative inhibition of Gnaz dampen the axon-repulsive response to Shh, and Gnaz mutant intestines contain centrally projected enteric axons. Together, our data uncover a previously unsuspected mechanism underlying development of centrifugal tubular organization and identify a previously unidentified effector of Shh in axon guidance.enteric neuron | axon guidance | chemorepellent | Hedgehog | Gas1

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Gene Targeting Reveals a Critical Role for Neurturin in the Development and Maintenance of Enteric, Sensory, and Parasympathetic Neurons

Cited by 298 publications

References 50 publications

Mice expressing a dominant-negative Ret mutation phenocopy human Hirschsprung disease and delineate a direct role of Ret in spermatogenesis

Mice expressing a dominant-negative Ret mutation phenocopy human Hirschsprung disease and delineate a direct role of Ret in spermatogenesis

The Candidate Neuroprotective Agent Artemin Induces Autonomic Neural Dysplasia without Preventing Peripheral Nerve Dysfunction

Gas1 is a receptor for sonic hedgehog to repel enteric axons

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