title: Ablation of RIC8A function in mouse neurons leads to a severe neuromuscular phenotype and postnatal death.
abstract: Resistance to inhibitors of cholinesterase 8 (RIC8) is a guanine nucleotide exchange factor required for the intracellular regulation of G protein signalling. RIC8 activates different Gα subunits via non-canonical pathway, thereby amplifying and prolonging the G protein mediated signal. In order to circumvent the embryonic lethality associated with the absence of RIC8A and to study its role in the nervous system, we constructed Ric8a conditional knockout mice using Cre/loxP technology. Introduction of a synapsin I promoter driven Cre transgenic mouse strain (SynCre) into the floxed Ric8a (Ric8a (F/F) ) background ablated RIC8A function in most differentiated neuron populations. Mutant SynCre (+/-) Ric8 (lacZ/F) mice were born at expected Mendelian ratio, but they died in early postnatal age (P4-P6). The mutants exhibited major developmental defects, like growth retardation and muscular weakness, impaired coordination and balance, muscular spasms and abnormal heart beat. Histological analysis revealed that the deficiency of RIC8A in neurons caused skeletal muscle atrophy and heart muscle hypoplasia, in addition, the sinoatrial node was misplaced and its size reduced. However, we did not observe gross morphological changes in brains of SynCre (+/-) Ric8a (lacZ/F) mutants. Our results demonstrate that in mice the activity of RIC8A in neurons is essential for survival and its deficiency causes a severe neuromuscular phenotype.
authors: Institute of Molecular and Cell Biology, University of Tartu, Tartu, Estonia. katrin86@ut.ee
authors: Katrin
authors: K
authors: Ruisu
authors: Keiu
authors: K
authors: Kask
authors: Riho
authors: R
authors: Meier
authors: Merly
authors: M
authors: Saare
authors: Raivo
authors: R
authors: Raid
authors: Alar
authors: A
authors: Veraksitš
authors: Alar
authors: A
authors: Karis
authors: Tambet
authors: T
authors: Tõnissoo
authors: Margus
authors: M
authors: Pooga
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001921:Brain / Q000473:pathology; D002454:Cell Differentiation; D017353:Gene Deletion; D020662:Guanine Nucleotide Exchange Factors / Q000172:deficiency / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology; D009133:Muscular Atrophy / Q000378:metabolism / Q000473:pathology; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D009469:Neuromuscular Junction / Q000378:metabolism* / Q000473:pathology*; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D009928:Organ Specificity; D010641:Phenotype; D012849:Sinoatrial Node / Q000378:metabolism / Q000473:pathology; D016019:Survival Analysis
chemical_list: D020662:Guanine Nucleotide Exchange Factors; C485884:Ric8a protein, mouse
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