Role of Elp1 in neural crest cell migration, differentiation and target tissue innervation in Familial Dysautonomia

Abstract

A highly conserved germline point mutation located in the donor splice site of intron 20 of the human Elp1 gene leads to loss of its encoded protein and causes familial dysautonomia (FD; Riley‐Day Syndrome; hereditary sensory and autonomic neuropathy, type 3; HSAN3), an autosomal recessive disease characterized by severe and progressive sympathetic and sensory neuron loss. The protein encoded by elp1 is required for development beyond mid‐gestation and it is part of the transcriptional elongator multi‐protein complex, but its functional role in disease pathogenesis remains poorly understood. To examine the role of elp1 in sympathetic and sensory neuron development, we generated conditional elp1 knockout mice and we used Wnt1‐Cre transgenic mice to ablate elp1 in neural crest (NC) cells, a highly migratory population of cells which gives rise to sympathetic, sensory and enteric neurons during development. Loss of elp1 in NC cells showed no impairment in their migration, but there was a significant impact on post‐migratory sensory and sympathetic neuron survival and target tissue innervation. In vitro studies using elp1‐deficient neurons showed that it has a profound impact on growth factor‐induced neurite outgrowth but no role in neuron survival. These results indicate that FD is not caused by impaired neuronal migration but rather, neuron death resulting from ineffective target tissue innervation.