RET is a single membrane tyrosine kinase receptor that mediates signaling of GDNF family ligands (GFLs) in association with GFRalpha coreceptors. Aberrant RET signaling results in a number of human diseases and developmental abnormalities, including multiple endocrine neoplasia type 2 syndromes, Hirschsprung disease (intestinal ganglionosis), and developmental abnormalities of the peripheral nervous and urogenital systems in mice. GFL signaling is also important for the survival of neuronal populations such as midbrain dopaminergic neurons and spinal cord motor neurons, which degenerate in Parkinson disease and amyotrophic lateral sclerosis (ALS), respectively. The molecular defects in the signaling pathways that result in the wide variety of RET-mediated abnormalities are largely unknown. This lack of knowledge is an impediment for the creation of rationally designed medical interventions for these conditions. Similar to other receptor tyrosine kinases (RTKs), RET signals through interactions between key phosphotyrosine docking sites and their cognate adaptor proteins. Signals emanating from these interactions are important in RET-mediated regulation of cellular processes such as proliferation, migration, and axonal outgrowth, whereas the perturbation of these processes ultimately leads to diseases. The candidate proposes to characterize mice expressing RET mutants lacking key adaptor docking sites in order to associate these mutations with alterations in key cellular processes that lead to developmental deficits in the peripheral nervous and urogenital systems. As aberrations in RET-stimulated proliferation is central to its role in tumorigenesis and developmental abnormalities, the candidate will utilize engineered fibroblast cell lines to study this aspect of RET biology in further detail. These in vitro assays will be used in conjunction with lentivirus delivery of specific siRNAs to identify signaling components (adaptor proteins) and pathways (MAPK, PLCgamma) that signal through particular RET docking sites to regulate proliferation. The identification of specific components of this signaling pathway will be helpful ultimately in developing targeted therapeutics for these tumors and in enhancing our understanding of nervous system development.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08HD047396-03
Application #
7106482
Study Section
Pediatrics Subcommittee (CHHD)
Program Officer
Henken, Deborah B
Project Start
2004-08-15
Project End
2009-07-31
Budget Start
2006-08-01
Budget End
2007-07-31
Support Year
3
Fiscal Year
2006
Total Cost
$148,446
Indirect Cost
Name
Washington University
Department
Surgery
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Jain, Sanjay; Knoten, Amanda; Hoshi, Masato et al. (2010) Organotypic specificity of key RET adaptor-docking sites in the pathogenesis of neurocristopathies and renal malformations in mice. J Clin Invest 120:778-90
Golden, Judith P; Hoshi, Masato; Nassar, Mohammed A et al. (2010) RET signaling is required for survival and normal function of nonpeptidergic nociceptors. J Neurosci 30:3983-94
Zhang, Bin; Chang, Jufang; Fu, Ming et al. (2009) Dosage effects of cohesin regulatory factor PDS5 on mammalian development: implications for cohesinopathies. PLoS One 4:e5232
Rozen, Esteban J; Schmidt, Hagen; Dolcet, Xavier et al. (2009) Loss of Sprouty1 rescues renal agenesis caused by Ret mutation. J Am Soc Nephrol 20:255-9
Encinas, M; Rozen, E J; Dolcet, X et al. (2008) Analysis of Ret knockin mice reveals a critical role for IKKs, but not PI 3-K, in neurotrophic factor-induced survival of sympathetic neurons. Cell Death Differ 15:1510-21
Wahrle, Suzanne E; Jiang, Hong; Parsadanian, Maia et al. (2008) Overexpression of ABCA1 reduces amyloid deposition in the PDAPP mouse model of Alzheimer disease. J Clin Invest 118:671-82
Brantley Jr, Milam A; Jain, Sanjay; Barr, Emily E et al. (2008) Neurturin-mediated ret activation is required for retinal function. J Neurosci 28:4123-35
Zhang, Bin; Jain, Sanjay; Song, Haengseok et al. (2007) Mice lacking sister chromatid cohesion protein PDS5B exhibit developmental abnormalities reminiscent of Cornelia de Lange syndrome. Development 134:3191-201
Jain, Sanjay; Suarez, Adrian A; McGuire, John et al. (2007) Expression profiles of congenital renal dysplasia reveal new insights into renal development and disease. Pediatr Nephrol 22:962-74
Uesaka, Toshihiro; Jain, Sanjay; Yonemura, Shigenobu et al. (2007) Conditional ablation of GFRalpha1 in postmigratory enteric neurons triggers unconventional neuronal death in the colon and causes a Hirschsprung's disease phenotype. Development 134:2171-81

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