Functional analysis of SOX11 and NF1 in sensory neuron development and plasticity

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Title: Functional analysis of SOX11 and NF1 in sensory neuron development and plasticity
Author: Lin, Lu
Abstract: Development of sensory neurons is controlled by both cell -extrinsic and cell -intrinsic factors . The transcription factor Sox11 is abundantly expressed in embryonic sensory neurons . In the first part of this thesis , by using a Sox11 - / - mouse model , I show that the loss of Sox11 results in increased cell death in embryonic sensory ganglia , which leads to a significant neuronal loss around birth . The ablation of Sox11 also leads to cell -death -independent axonal growth defects both in vivo and in vitro . Furthermore , I demonstrate that Sox11 -deficient MEFs exhibit decreased level of phospho -AKT compared to controls . These data suggest that Sox11 is required for multiple key steps of sensory neuron development , probably through regulating the expression of component (s ) of the signaling pathways downstream of growth factors . Adult sensory neurons exhibit various degrees of plasticity following different types of injury . Neurofibromin , the protein encoded by the tumor suppressor gene Nf1 , functions as a negative regulator of Ras and its two major downstream pathways : MEK -ERK and PI3K -Akt pathway . Nf1 - / - embryonic sensory neurons survive without neurotrophin support attributed to enhanced PI3K activity in the absence of Nf1 . In the second part of this thesis , by using mice with Nf1 specifically deleted in neurons (Nf1 -SynI -CKO ) , I demonstrate that Nf1 - / - adult sensory neurons exhibit enhanced neurite outgrowth in vitro . After dorsal root injury , spontaneous functional recovery and increased axonal sprouting from uninjured sensory neurons are observed in Nf1 -SynI -CKO mice compared to permanent sensory deficits in controls . These appear to be mediated both by cell autonomous capacity of spared Nf1 - / - DRG neurons and by non -cell autonomous contribution from Nf1 - / - neurons in the spinal cord , as suggested by co -culture experiments . To further confirm whether the spinal cord or DRG neurons contribute to functional recovery in Nf1 -SynI -CKO mice , I generated other mutants with Nf1 deleted more specifically and completely in DRG (Nf1 -Isl1 -CKO ) . In the third part of this thesis , I discuss some unanticipated results due to Cre expression in the gastrointestinal tract . Nf1 -Isl1 -CKO mice develop gastric epithelium hyperplasia and inflammation with increased proliferation and apoptosis . These phenotypes seem to be attributed to the loss of Nf1 in non -gastric epithelial cells .
URI: http : / /hdl .handle .net /2152 .5 /582
Date: 2009-01-14

Citation

Functional analysis of SOX11 and NF1 in sensory neuron development and plasticity. Graduate School of Biomedical Sciences. Available electronically from http : / /hdl .handle .net /2152 .5 /582 .

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