Differential expression of the GDNF family receptors RET and GFRα1, 2, and 4 in subsets of motoneurons: A relationship between motoneuron birthdate and receptor expression

Homma, Shunsaku; Yaginuma, Hiroyuki; Vinsant, Sharon; Seino, Miho; Kawata, Megumi; Gould, Thomas W.; Shimada, Takako; Kobayashi, Nobumi; Oppenheim, Ronald W.

doi:10.1002/cne.10529

Cited by 25 publications

(24 citation statements)

References 86 publications

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“…Thus, Ret DN/+ mice have deficits in SPG neuron number, size and target innervation that are a combination of the defects observed in GDNF-and NRTN-null mice, supporting the hypothesis that persistent Ret signaling is required for both the formation and proper function of SPG neurons. The previous analysis of Ret -/-and ARTN -/-mice revealed that Ret signaling is also important for sympathetic neuron precursor migration and neuronal projections (Enomoto et al, 2001;Homma et al, 2003). In Ret DN/+ mice, we found that, in contrast to in ARTN-and Ret-null mice, the SCG was properly located and had normal axonal projections to its targets (Fig.…”

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

confidence: 48%

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/+ Micesupporting

confidence: 48%

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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“…Thus, even if motor neurons innervate the inappropriate muscle in older donor limbs, they most likely would be exposed to GDNF. This finding suggests that the expression of Pea3 in just three motor pools most likely reflects the pool-specific expression of GDNF receptor ␣ family members (Homma et al, 2003), rather than the restricted expression of GDNF in the target. The restriction of Er81 to the appropriate motor neurons following a variety of surgical manipulations that mismatched motor neurons and the periphery (Wang and Scott, 2004) suggests that Er81 expression is constrained by similar mechanisms, although the peripheral signals and their receptors remain to be elucidated.…”

Section: Restriction Of Ets Expression To Appropriate Motor Poolsmentioning

confidence: 94%

“…Pea3 expression is induced by GDNF, which is widely expressed in hindlimb muscles (Homma et al, 2003). Thus, even if motor neurons innervate the inappropriate muscle in older donor limbs, they most likely would be exposed to GDNF.…”

Section: Restriction Of Ets Expression To Appropriate Motor Poolsmentioning

confidence: 99%

Onset of ETS expression is not accelerated by premature exposure to signals from limb mesenchyme

Wang

Scott

2007

Developmental Dynamics

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“…Previous analysis of Ret-null and Artemin-null mice showed that Ret signaling is important for sympathetic neuron precursor migration and axonal projection (10,30). In these mutants, the SCG fails to migrate to its proper location, resulting in accompanying abnormalities in projections to the submandibular gland and muscles of the eye.…”

Section: Figurementioning

confidence: 99%

Organotypic specificity of key RET adaptor-docking sites in the pathogenesis of neurocristopathies and renal malformations in mice

Jain¹,

Knoten²,

Hoshi³

et al. 2010

J. Clin. Invest.

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The receptor tyrosine kinase ret protooncogene (RET) is implicated in the pathogenesis of several diseases and in several developmental defects, particularly those in neural crest-derived structures and the genitourinary system. In order to further elucidate RET-mediated mechanisms that contribute to these diseases and decipher the basis for specificity in the pleiotropic effects of RET, we characterized development of the enteric and autonomic nervous systems in mice expressing RET9 or RET51 isoforms harboring mutations in tyrosine residues that act as docking sites for the adaptors Plcγ, Src, Shc, and Grb2. Using this approach, we found that development of the genitourinary system and the enteric and autonomic nervous systems is dependent on distinct RET-stimulated signaling pathways. Thus, mutation of RET51 at Y1062, a docking site for multiple adaptor proteins including Shc, caused distal colon aganglionosis reminiscent of Hirschsprung disease (HSCR). On the other hand, this mutation in RET9, which encodes an isoform that lacks the Grb2 docking site present in RET51, produced severe abnormalities in multiple organs. Mutations that abrogate RET-Plcγ binding, previously shown to produce features reminiscent of congenital anomalies of kidneys or urinary tract (CAKUT) syndrome, produced only minor abnormalities in the nervous system. Abrogating RET51-Src binding produced no major defects in these systems. These studies provide insight into the basis of organotypic specificity and redundancy in RET signaling within these unique systems and in diseases such as HSCR and CAKUT.

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Differential expression of the GDNF family receptors RET and GFRα1, 2, and 4 in subsets of motoneurons: A relationship between motoneuron birthdate and receptor expression

Cited by 25 publications

References 86 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

Onset of ETS expression is not accelerated by premature exposure to signals from limb mesenchyme

Organotypic specificity of key RET adaptor-docking sites in the pathogenesis of neurocristopathies and renal malformations in mice

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