Journal ArticleDOI
Evolution of the GDNF family ligands and receptors.
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TLDR
The presence of RET- and GFR-like genes in insects suggests that a ProtoGFR and a ProtoRET arose early in the evolution of bilaterian animals, but when the ProtoGFL diverged from existing transforming growth factor (TGFβ)-like proteins remains unclear.Abstract:
Four different ligand-receptor binding pairs of the GDNF (glial cell line-derived neurotrophic factor) family exist in mammals, and they all signal via the transmembrane RET receptor tyrosine kinase. In addition, GRAL (GDNF Receptor Alpha-Like) protein of unknown function and Gas1 (growth arrest specific 1) have GDNF family receptor (GFR)-like domains. Orthologs of the four GFRα receptors, GRAL and Gas1 are present in all vertebrate classes. In contrast, although bony fishes have orthologs of all four GDNF family ligands (GFLs), one of the ligands, neurturin, is absent in clawed frog and another, persephin, is absent in the chicken genome. Frog GFRα2 has selectively evolved possibly to accommodate GDNF as a ligand. The key role of GDNF and its receptor GFRα1 in enteric nervous system development is conserved from zebrafish to humans. The role of neurturin, signaling via GFRα2, for parasympathetic neuron development is conserved between chicken and mice. The role of artemin and persephin that signal via GFRα3 and GFRα4, respectively, is unknown in non-mammals. The presence of RET- and GFR-like genes in insects suggests that a ProtoGFR and a ProtoRET arose early in the evolution of bilaterian animals, but when the ProtoGFL diverged from existing transforming growth factor (TGFβ)-like proteins remains unclear. The four GFLs and GFRαs were presumably generated by genome duplications at the origin of vertebrates. Loss of neurturin in frog and persephin in chicken suggests functional redundancy in early tetrapods. Functions of non-mammalian GFLs and prechordate RET and GFR-like proteins remain to be explored.read more
Citations
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Journal ArticleDOI
RET revisited: expanding the oncogenic portfolio
TL;DR: The complex roles of RET in homeostasis and survival of neural lineages and in tumour-associated inflammation might also suggest potential long-term pitfalls of broadly targeting RET.
Journal ArticleDOI
Specificity, versatility, and control of TGF-β family signaling.
Rik Derynck,Erine H. Budi +1 more
TL;DR: The exquisite nature of TGF-β family signaling in its roles in diverse and context-specific cellular behaviors is described and the mechanisms through which proteins called Smads act as intracellular effectors of ligand-induced gene expression responses are introduced, showing that the specificity and impressive versatility of Smad signaling depend on cross-talk from other pathways.
Journal ArticleDOI
GFRAL is the receptor for GDF15 and is required for the anti-obesity effects of the ligand
Linda Yang,Chih-Chuan Chang,Zhe Sun,Dennis Madsen,Haisun Zhu,Søren Berg Padkjær,Xiaoai Wu,Tao Huang,Karin Hultman,Sarah J Paulsen,Jishu Wang,Anne Bugge,Jane Boesen Frantzen,Per Nørgaard,Jacob Jeppesen,Zhiru Yang,Anna Secher,Haibin Chen,Xun Li,Linu M. John,Bing Shan,Zhenhua He,Xiang Gao,Jing Su,Kristian Tage Hansen,Wei Yang,Sebastian Beck Jørgensen +26 more
TL;DR: It is shown that GDF15 binds specifically to GDNF family receptor α-like (GFRAL) with high affinity, and that GFRAL requires association with the coreceptor RET to elicit intracellular signaling in response to GDF 15 stimulation.
Journal ArticleDOI
The metabolic effects of GDF15 are mediated by the orphan receptor GFRAL
Paul J. Emmerson,Feng Wang,Yong Du,Qian Liu,Richard Todd Pickard,Malgorzata Donata Gonciarz,Tamer Coskun,Matthew J Hamang,Dana Sindelar,Kimberly K Ballman,Lisa A Foltz,Avinash Muppidi,Jorge Alsina-Fernandez,Gavin C. Barnard,Jason X. Tang,Xilin Liu,Xudong Mao,Robert W. Siegel,John H. Sloan,Pamela Jean Mitchell,Bei B Zhang,Ruth E. Gimeno,Bei Shan,Xinle Wu +23 more
TL;DR: It is demonstrated that GDNF-family receptor α-like (GFRAL), an orphan member of the GFR-α family, is a high-affinity receptor for GDF15 that mediates the metabolic effects of GDF12 and binds to GDF 15 in vitro and is required for the metabolic actions of G DF15 with respect to body weight and food intake in vivo in mice.
Journal ArticleDOI
Overlapping Roles and Collective Requirement for the Coreceptors GAS1, CDO, and BOC in SHH Pathway Function
Benjamin L. Allen,Benjamin L. Allen,Jane Y. Song,Luisa Izzi,Luisa Izzi,Irene W. Althaus,Jong-Sun Kang,Frédéric Charron,Frédéric Charron,Robert S. Krauss,Andrew P. McMahon +10 more
TL;DR: Evidence is provided that GAS1, CDO, and BOC play overlapping and essential roles during HH-mediated ventral neural patterning of the mammalian neural tube and an early role in cell fate specification of multiple neural progenitors and a later role in motor neuron progenitor maintenance.
References
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Journal ArticleDOI
GDNF: a glial cell line-derived neurotrophic factor for midbrain dopaminergic neurons
TL;DR: In embryonic midbrain cultures, recombinant human GDNF promoted the survival and morphological differentiation of dopaminergic neurons and increased their high-affinity dopamine uptake and did not increase total neuron or astrocyte numbers or transmitter uptake.
Journal ArticleDOI
The GDNF family: Signalling, biological functions and therapeutic value
Matti S. Airaksinen,Mart Saarma +1 more
TL;DR: Members of the nerve growth factor and glial cell line-derived neurotrophic factor families — comprising neurotrophins and GDNF-family ligands (GFLs) — are crucial for the development and maintenance of distinct sets of central and peripheral neurons.
Journal ArticleDOI
Defects in the kidney and enteric nervous system of mice lacking the tyrosine kinase receptor Ret
Anita Schuchardt,Vivette D. D'Agati,Lena Larsson-Blomberg,Frank Costantini,Vassilis Pachnis,Vassilis Pachnis +5 more
TL;DR: It is shown that mice homozygous for a targeted mutation in c-ret develop to term, but die soon after birth, showing renal agenesis or severe dysgenesis, and lacking enteric neurons throughout the digestive tract, indicating an essential component of a signalling pathway required for renal organogenesis and enteric neurogenesis.
Journal ArticleDOI
Regulation of cell fate decision of undifferentiated spermatogonia by GDNF.
Xiaojuan Meng,Maria Lindahl,Mervi E. Hyvönen,Martti Parvinen,Dirk G. de Rooij,Michael W. Hess,Anne Raatikainen-Ahokas,Kirsi Sainio,Heikki Rauvala,Merja Lakso,José G. Pichel,Heiner Westphal,Mart Saarma,Hannu Sariola +13 more
TL;DR: Transgenic loss-of-function and overexpression models show that the dosage of glial cell line-derived neurotrophic factor (GDNF), produced by Sertoli cells, regulates cell fate decisions of undifferentiated sperMatogonial cells that include the stem cells for spermatogenesis.
Journal ArticleDOI
Renal and neuronal abnormalities in mice lacking GDNF.
Mark W. Moore,Robert D. Klein,Isabel Fariñas,Hansjorg Sauer,Mark Armanini,Heidi S. Phillips,Louis F. Reichardt,Anne M. Ryan,Karen Carver-Moore,Arnon Rosenthal +9 more
TL;DR: It is shown that at postnatal day 0 (P0), GDNF-deficient mice have deficits in dorsal root ganglion, sympathetic and nodose neurons, but not in hindbrain noradrenergic or midbrain dopaminergic neurons, and GDNF is important for the development and/or survival of enteric, sympathetic, and sensory neurons and the renal system, but is not essential for catecholaminergic neuron in the central nervous system (CNS).
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