Point Mutation in Exon 12 of  the Receptor Tyrosine Kinase Proto-oncogene RET in Ondine-Hirschsprung Syndrome

Sakai, Tetsuo; Wakizaka, Akira; Matsuda, Hiroki; Nirasawa, Yuji; Itoh, Yasuo

doi:10.1542/peds.101.5.924

Cited by 62 publications

(29 citation statements)

References 22 publications

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“…Recent reports support a role for GDNF dysfunction in at least one developmental abnormality of respiratory control in humans, congenital central hypoventilation syndrome (CCHS; or Ondine's Curse). CCHS is characterized by depressed and irregular breathing and diminished chemical drive, and point mutations in the GDNF and RET genes have each been found in cases of CCHS (Amiel et al, 1998;Sakai et al, 1998). Moreover, newborn mice lacking RET exhibit depressed ventilatory responses to 10% CO 2 (Burton et al, 1997).…”

Section: Discussionmentioning

confidence: 99%

Brain-Derived Neurotrophic Factor and Glial Cell Line-Derived Neurotrophic Factor Are Required Simultaneously for Survival of Dopaminergic Primary Sensory NeuronsIn Vivo

2001

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Null mutations affecting members of the transforming growth factor-␤ and neurotrophin families result in overlapping patterns of neuronal cell death. This is particularly striking in the cranial sensory nodose-petrosal ganglion complex (NPG), in which loss of either glial cell line-derived neurotrophic factor (GDNF), brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), or neurotrophin-4 (NT-4) results in a 30-50% reduction in neuronal survival. It is unknown, however, whether GDNF and any single neurotrophin support survival of the same cells, and if so, whether they are required simultaneously or sequentially during development. To approach these issues we defined survival requirements of nodose and petrosal neurons for GDNF in vitro and in bdnf, gdnf, and bdnf/gdnf null mutant mice, as well as the distribution of GDNF in NPG target tissues. Our analyses focused on the total population of ganglion cells as well as the subset of NPG neurons that are dopaminergic.Neuron losses in bdnf/gdnf double mutants are not additive of the losses in single bdnf or gdnf null mutants, indicating that many cells, including dopaminergic neurons, require both GDNF and BDNF for survival in vivo. Moreover, both factors are required during the same period of development, between embryonic day (E) 15.5 and E17.5. In addition, GDNF, like BDNF is expressed in target tissues at the time of initial target innervation and coincident with GDNF dependence of the innervating neurons. Together, these findings demonstrate that both GDNF and BDNF can act as target-derived trophic factors and are required simultaneously for survival of some primary sensory neurons. Key words: GDNF; BDNF; primary sensory neurons; growth factors; neurotrophins; knock-out mice; nodose ganglion; petrosal ganglion; carotid bodyGlial cell line-derived neurotrophic factor (GDNF) and the related proteins neurturin, persephin, and artemin, comprise a subgroup of the transforming growth factor-␤ superfamily of growth and differentiation factors. The GDNF family members signal through a receptor complex consisting of a ligand-specific glycosyl-phosphatidylinositol-linked binding molecule (GFR␣) and the membrane-spanning RET (rearranged during transfection) receptor tyrosine kinase (Rosenthal, 1999;Baloh et al., 2000). GDNF supports survival of a variety of peripheral and central neurons in vitro, including midbrain dopaminergic, spinal motor, sympathetic, parasympathetic, peripheral sensory, and enteric neurons (for review, see Unsicker et al., 1998). However, analysis of GDNF or GFR␣1 knock-out mice has revealed that a more restricted subset of neurons requires GDNF for survival in vivo Pichel et al., 1996;Sanchez et al., 1996;Cacalano et al., 1998).One of the most severely affected neuronal populations in GDNF knock-out mice is the nodose-petrosal ganglion complex (NPG) of primary cranial sensory neurons, in which 40% of cells die by birth . Interestingly, targeted disruption of the genes encoding brain-derived neurotrophic factor (BDNF) (Ernfors et al., 1994...

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Section: Discussionmentioning

confidence: 99%

Brain-Derived Neurotrophic Factor and Glial Cell Line-Derived Neurotrophic Factor Are Required Simultaneously for Survival of Dopaminergic Primary Sensory NeuronsIn Vivo

2001

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“…ECE-1) have been shown to be involved in CCHS and/or HSCR. Mutations in RET or its ligands (GDNF and neurturin) have been reported in two cases of CCHS, one with and one without HSCR (38,39). In addition, a mutation in endothelin-3 has been found in one patient with CCHS (40).…”

Section: Involvement Of Neural Crest Derivatives In Early Impairmentsmentioning

confidence: 98%

Impaired Ventilatory Responses to Hypoxia in Mice Deficient in Endothelin-Converting-Enzyme-1

et al. 2001

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Endothelin-converting-enzyme (ECE-1) catalyzes the proteolytic activation of big endothelin-1 to mature endothelin-1. Most homozygous ECE-1Ϫ/Ϫ embryos die in utero and show severe craniofacial, enteric, and cardiac malformations precluding ventilatory function assessment. In contrast, heterozygous ECE-1ϩ/Ϫ embryos develop normally. Their respiratory function at birth has not been studied. Taking into account previous respiratory investigations in mice with endothelin-1 gene disruption, we hypothesized that ECE-1-deficient mice may have impaired ventilatory control. We analyzed ventilatory responses to hypercapnia (8% CO 2 ) and hypoxia (10% O 2 ) in newborn and adult mice heterozygous for ECE-1 deficiency (ECE-1ϩ/Ϫ) and in their wild-type littermates (ECE-1ϩ/ϩ). Ventilation, breath duration, and tidal volume were measured using whole-body plethysmography. Ventilatory responses to hypoxia were significantly weaker in ECE-1ϩ/Ϫ than in ECE-1ϩ/ϩ newborn mice (percentage ventilation increase: 1 Ϯ 25% versus 33 Ϯ 29%, p ϭ 0.010). Baseline breathing variables and ventilatory responses to hypercapnia were normal in the ECE-1ϩ/Ϫ newborn mice. No differences were observed between adult ECE-1ϩ/Ϫ and ECE-1ϩ/ϩ mice. We conclude that ECE-1 is required for normal ventilatory response to hypoxia at birth. Abbreviations CCHS, congenital central hypoventilation syndrome ECE-1, endothelin-converting-enzyme-1 ET-1, endothelin-1 GDNF, glial-cell-line-derived neurotrophic factor HSCR, Hirschsprung's disease NTS, nucleus tractus solitarius RET, rearranged during transfection TTOT, breath duration VE, ventilation VT, tidal volume ECE-1 catalyzes the proteolytic activation of big ET-1 to mature ET-1 (1, 2). Targeted ECE-1 gene disruption, which has recently been achieved in mice, has important effects on embryonic development and autonomic functions (3). Among homozygous ECE-1Ϫ/Ϫ embryos, most die in utero (about 75% in a C57BL/6 -129SvEv hybrid background) and all exhibit craniofacial, enteric, and cardiac malformations (3) that preclude valid ventilatory function assessment. In contrast, heterozygous ECE-1ϩ/Ϫ newborns are apparently healthy and develop normally. In a recent study, the differences in respiratory function between adult heterozygous ECE-1ϩ/Ϫ and wild-type ECE-1ϩ/ϩ adult mice were found to be not significant (4). Newborn mice were not studied. In the present study, we tested the ventilatory responses to chemical stimuli in heterozygous ECE-1ϩ/Ϫ newborn mice, and we reexamined the normality of adult heterozygous ECE-1ϩ/Ϫ mice in a larger sample of mice than previously done (4).Our working hypothesis was based on previous data showing that ET-1 is required for normal ventilatory control. First, in anesthetized rats, topical applications of ET-1 in the chemosensitive area of the ventral medulla oblongata and other areas involved in respiratory control cause changes in phrenic nerve activity (2). Specifically, applications of ET-1 in regions extending between the caudal end of the trapezoid body and the rootlets of the XIIth ...

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“…Likewise, the central respiratory controller, which regulates autonomic ventilation, is derived at least in part from the neural crest, because some cases of congenital central hypoventilation syndrome are associated with mutations of the gene coding for the receptor tyrosine kinase REarranged during Transfection (RET) (Amiel et al 1998;Sakai et al 1998;Kanai et al 2002). Congenital central hypoventilation syndrome is defined as the failure of automatic control of breathing, and is characterized by the marginal ventilatory sensitivity to hypoxia and hypercapnia during sleep (Amiel et al 1998;Sakai et al 1998;Kanai et al 2002). In fact, chemical control of respiration, in response to both hypercapnia and hypoxia, tend to be blunted during sleep (Fig.…”

Section: Altered Ventilatory Responses In Bw Mice Lacking Melanocytesmentioning

confidence: 99%

Neuroendocrine Functions of Melanocytes: Beyond the Skin-Deep Melanin Maker

Takeda

Takahashi

Shibahara

2007

Tohoku J. Exp. Med.

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The skin is armored with "dead cells", the stratum corneum, and is continuously exposed to external stressful environments, such as atmospheric oxygen, solar radiations, and thermal and chemical insults. Melanocytes of neural crest origin are located in the skin, eye, inner ear, and leptomeninges. Melanin pigment in the skin is produced by melanocytes under the influence of various endogenous factors, derived from neighboring keratinocytes and underlying fibroblasts. The differentiation and functions of melanocytes are regulated at multiple processes, including transcription, RNA editing, melanin synthesis, and the transport of melanosomes to keratinocytes. Impairment at each step causes the pigmentary disorders in humans, with the historical example of oculocutaneous albinism. Moreover, heterozygous mutations in the gene coding for microphthalmia-associated transcription factor, a key regulator for melanocyte development, are associated with Waardenburg syndrome type 2, an auditory-pigmentary disorder. Sun tanning, melasma, aging spots (lentigo senilis), hair graying, and melanoma are well-known melanocyte-related pathologies. Melanocytes therefore have attracted much attention of many ladies, makeup artists and molecular biologists. More recently, we have shown that lipocalin-type prostaglandin D synthase (L-PGDS) is expressed in melanocytes but not in other skin cell types. L-PGDS generates prostaglandin D 2 and also functions as an inter-cellular carrier protein for lipophilic ligands, such as bilirubin and thyroid hormones. Thus, melanocytes may exert hitherto unknown functions through L-PGDS and prostaglandin D 2 . Here we update the neuroendocrine functions of melanocytes and discuss the possible involvement of melanocytes in the control of the central chemosensor that generates respiratory rhythm.heme; hypoxia; lipocalin-type prostaglandin D synthase; melanocyte; microphthalmia-associated transcription factor

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Point Mutation in Exon 12 of the Receptor Tyrosine Kinase Proto-oncogene RET in Ondine-Hirschsprung Syndrome

Cited by 62 publications

References 22 publications

Brain-Derived Neurotrophic Factor and Glial Cell Line-Derived Neurotrophic Factor Are Required Simultaneously for Survival of Dopaminergic Primary Sensory NeuronsIn Vivo

Brain-Derived Neurotrophic Factor and Glial Cell Line-Derived Neurotrophic Factor Are Required Simultaneously for Survival of Dopaminergic Primary Sensory NeuronsIn Vivo

Impaired Ventilatory Responses to Hypoxia in Mice Deficient in Endothelin-Converting-Enzyme-1

Neuroendocrine Functions of Melanocytes: Beyond the Skin-Deep Melanin Maker

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