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Kirmo Wartiowaara

Bio: Kirmo Wartiowaara is an academic researcher. The author has contributed to research in topics: Receptor tyrosine kinase & Neurotrophic factors. The author has an hindex of 1, co-authored 1 publications receiving 812 citations.

Papers
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Journal ArticleDOI
27 Jun 1996-Nature
TL;DR: It is shown that glial-cell-line-derived neurotrophic factor (GDNF)7, a distant member of the transforming growth factor(TGF)-β superfamily, signals through the Ret RTK, and that GDNF, in addition to its potential role in the differentiation and survival of central nervous system neurons8–12, has profound effects on kidney organogenesis and the development of the peripheral nervous system.
Abstract: MUTATIONAL analysis in humans and mice has demonstrated that Ret, the product of the c-ret proto-oncogene, a member of the receptor tyrosine kinase (RTK) superfamily1, is essential for development of the enteric nervous system and kidney2–6. Despite the established role of Ret in mammalian embryogenesis, its cognate ligand(s) is currently unknown. Here we demonstrate, by using a Xenopus embryo bioassay, that glial-cell-line-derived neurotrophic factor (GDNF)7, a distant member of the transforming growth factor(TGF)-β superfamily, signals through the Ret RTK. Furthermore, using explant cultures from wild-type and Ret-deficient mouse embryos4, we show that normal c-ret function is necessary for GDNF signalling in the peripheral nervous system. Our data strongly suggest that Ret is a functional receptor for GDNF, and that GDNF, in addition to its potential role in the differentiation and survival of central nervous system neurons8–12, has profound effects on kidney organogenesis and the development of the peripheral nervous system.

831 citations


Cited by
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Journal ArticleDOI
TL;DR: Isolated HSCR appears to be a non-Mendelian malformation with low, sex-dependent penetrance, and variable expression according to the length of the aganglionic segment, which stands as a model for genetic disorders with complex patterns of inheritance.
Abstract: Hirschsprung disease (HSCR, aganglionic megacolon) represents the main genetic cause of functional intestinal obstruction with an incidence of 1/5000 live births. This developmental disorder is a neurocristopathy and is characterised by the absence of the enteric ganglia along a variable length of the intestine. In the last decades, the development of surgical approaches has importantly decreased mortality and morbidity which allowed the emergence of familial cases. Isolated HSCR appears to be a non-Mendelian malformation with low, sex-dependent penetrance, and variable expression according to the length of the aganglionic segment. While all Mendelian modes of inheritance have been described in syndromic HSCR, isolated HSCR stands as a model for genetic disorders with complex patterns of inheritance. The tyrosine kinase receptor RET is the major gene with both rare coding sequence mutations and/or a frequent variant located in an enhancer element predisposing to the disease. Hitherto, 10 genes and five loci have been found to be involved in HSCR development.

1,109 citations

Journal ArticleDOI
TL;DR: It is shown that Wnt9b is expressed in the inductive epithelia and is essential for the development of mesonephric and metanephric tubules and caudal extension of the Müllerian duct, and this data implicate canonical Wnt signaling as one of the major pathways in the organization of the mammalian urogenital system.

807 citations

Journal ArticleDOI
01 Oct 1997-Neuron
TL;DR: These findings suggest that IB4-binding neurons switch from dependence on NGF in embryonic life to dependence onGDNF in postnatal life and are likely regulated by GDNF in maturity.

746 citations

Journal ArticleDOI
05 Dec 1996-Nature
TL;DR: Neurturin and Glial Cell Line-derived neurotrophic factor (GDNF) as discussed by the authors have been shown to activate the MAP kinase signalling pathway in cultured sympathetic neurons and support the survival of sympathetic neurons, as well as of sensory neurons of nodose and dorsal root ganglia.
Abstract: The normal development of the vertebrate nervous system entails the death of 30-70% of the neurons originally generated in most neuronal populations. This naturally occurring cell death is regulated by specific neurotrophic factors that promote neuronal survival and which are produced in limiting quantities by target cells, glial cells and neurons. These factors are also of potential utility as therapeutic agents for neurodegenerative diseases. Here we describe the purification and cloning of a new neurotrophic factor, identified on the basis of its ability to support the survival of sympathetic neurons in culture. This factor, neurturin, is structurally related to glial-cell-line-derived neurotrophic factor (GDNF). These factors can each activate the MAP kinase signalling pathway in cultured sympathetic neurons and support the survival of sympathetic neurons, as well as of sensory neurons of the nodose and dorsal root ganglia. Thus, neurturin and GDNF together now define a new family of neurotrophic factors.

722 citations

Journal ArticleDOI
TL;DR: The results indicate that Eya1 controls critical early inductive signalling events involved in ear and kidney formation and integrate Eya2 into the genetic regulatory cascade controlling kidney formation upstream of Gdnf and suggest that an evolutionarily conserved Pax-Eya-Six regulatory hierarchy is used in mammalian ear and kidneys development.
Abstract: Haploinsufficiency for human EYA1, a homologue of the Drosophila melanogaster gene eyes absent (eya), results in the dominantly inherited disorders branchio-oto-renal (BOR) syndrome1,2,3 and branchio-oto (BO) syndrome4, which are characterized by craniofacial abnormalities and hearing loss with (BOR) or without (BO) kidney defects. To understand the developmental pathogenesis of organs affected in these syndromes, we inactivated the gene Eya1 in mice. Eya1 heterozygotes show renal abnormalities and a conductive hearing loss similar to BOR syndrome, whereas Eya1 homozygotes lack ears and kidneys due to defective inductive tissue interactions and apoptotic regression of the organ primordia. Inner ear development in Eya1 homozygotes arrests at the otic vesicle stage and all components of the inner ear and specific cranial sensory ganglia fail to form. In the kidney, Eya1 homozygosity results in an absence of ureteric bud outgrowth and a subsequent failure of metanephric induction. Gdnf expression, which is required to direct ureteric bud outgrowth via activation of the c-ret Rtk (refs 5, 6, 7, 8), is not detected in Eya1–/– metanephric mesenchyme. In Eya1–/– ear and kidney development, Six but not Pax expression is Eya1 dependent, similar to a genetic pathway elucidated in the Drosophila eye imaginal disc. Our results indicate that Eya1 controls critical early inductive signalling events involved in ear and kidney formation and integrate Eya1 into the genetic regulatory cascade controlling kidney formation upstream of Gdnf. In addition, our results suggest that an evolutionarily conserved Pax-Eya-Six regulatory hierarchy is used in mammalian ear and kidney development.

687 citations