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Title: The role of Arkadia2C and the BMP signalling pathway in motor neuron development
Author: Kelly, Claire Elizabeth
ISNI:       0000 0004 2710 3325
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2011
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Motor neurons elongate axons over great distances during development, with some extending from the spinal cord to the distal limb, but little is known about extracellular signals that control this growth. The TGF-β superfamily includes two major classes of ligands: Nodallike and BMP. BMP signalling is essential for neuromuscular synaptic growth and plasticity in Drosophila; however, a similar role for the pathway in mammalian motor neurons has not been described. It has previously been shown that the E3-RING ubiquitin ligase Arkadia enhances signalling through the Nodal branch of TGF-β signalling. A second Arkadia locus was previously found to contain two isoforms; the C-terminal isoform (Arkadia2C) contains domains critical for Arkadia’s activity. This project addresses the in vivo function of Arkadia2C in mice. Arkadia2C was found to be expressed specifically in the nervous system throughout embryonic development and adulthood. In a neuronal context Arkadia2C enhances signalling through the Smad1/5/8 branch of the TGF-β pathway in a RING domain-dependent manner. Mice null for Arkadia2C display motor neuron disease-like symptoms including weak motor control and difficulties breathing and eating, leading to postnatal mortality in the majority of mice. A subset of Arkadia2C null embryonic innervation defects was analysed; the majority of the motor axons of the dorsal forelimb fail to form synapses with their target muscles while the phrenic nerve exhibits shorter terminal branches. Postnatally, a failure to maintain neuromuscular junctions was observed leading to atrophy of several muscles. Active BMP signalling was observed in the neurons that innervate the limb and diaphragm and genetic reduction of BMP signalling in asymptomatic Arkadia2C heterozygous mice caused the appearance of the same muscle innervation defects observed in the null individuals. Together, these findings suggest that Arkadia2C’s enhancement of the BMP signalling pathway is critical for the growth and connectivity of certain motor neurons.
Supervisor: Episkopou, Vasso Sponsor: Medical Research Council
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral