Phenotypic Analysis of Motor Defects in Neuronal Ostm1 Conditional Loss of Function

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" Phenotypic Analysis of Motor Defects in Neuronal Ostm1 Conditional Loss of Function "
Hassan, Milhem Hajj Vacher, Jean

Document Type	:	Latin Dissertation
Language of Document	:	English
Record Number	:	1112066
Doc. No	:	TLpq2515625160
Main Entry	:	Hassan, Milhem Hajj
	:	Vacher, Jean
Title & Author	:	Phenotypic Analysis of Motor Defects in Neuronal Ostm1 Conditional Loss of Function\ Hassan, Milhem HajjVacher, Jean
College	:	McGill University (Canada)
Date	:	2020
student score	:	2020
Degree	:	M.Sc.
Page No	:	100
Abstract	:	Mutations in the human and mouse Ostm1/Ostm1 gene result in the most severe form of autosomal recessive osteopetrosis, an inherited hematopoietic bone disorder. We isolated and characterized the Ostm1 gene responsible for the spontaneous murine osteopetrotic gl mutation and functional rescue of hematopoietic defects was obtained in PU.1-Ostm1 gl/gl BAC transgenic mice. However, these transgenic gl/gl mice became overtly ill and died prematurely around 6-7 weeks with severe neurodegeneration associated with impaired autophagy. To investigate whether Ostm1 has a direct role in neuronal cells, we generated a conditional Ostm1lox/lox allele to address the Ostm1 neuronal specificity with Synapsin1-Cre loss of function. Ostm1lox/lox SYN1-Cre+ progenies developed normally until ~7 weeks and were undistinguishable from control littermates. Around ~8-9 weeks of age Ostm1lox/lox Synapsin1-Cre+ mice developed a rapid and progressive neuronal deficit. These mice showed abnormal limb-clasping reflexes, severe motor defects and stopped gaining weight. Consistently, brain histology revealed inflammatory response with gliosis, loss of neuronal cells in CA3 and dentate gyrus of the hippocampus and thinning of the cortex. Spinal cord EM analysis showed axonal swelling with accumulation of vesicular structures similar to autophagosomes. End-stage disease is characterized by hind limbs paralysis consistent with reduced motor neurons population, neuromuscular junctions’ pathology and muscle fiber atrophy. Together, our results provided evidence that the Ostm1 plays a major role in neuronal homeostasis and further establish an Ostm1 neuromuscular crosstalk.
Subject	:	Brain research
	:	Genetics
	:	Mutation
	:	Neurobiology
	:	Neurodegeneration
	:	Physiology