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

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.