The role of RIC8A in the development and regulation of mouse nervous system
Date
2017-05-22
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Abstract
Kesknärvisüsteemi ja perifeerse närvisüsteemi korrektne toimimine on ülioluline organismi täisväärtusliku elu tagamiseks. Seetõttu on närvisüsteemi arengus rangelt kontrollitud ja reguleeritud nii neuraalsete eellasrakkude ja neuronite teke, kui ka korrektne paigutumine ja võrgustike loomine. Neid protsesse koordineerivad mitmed signaalirajad, millest G-valkude (guaniin-nukleotiidi siduvad valgud) poolt vahendatud signaaliülekanne rakuvälise ja rakusisese keskkonna vahel on üks levinumaid mehhanisme närvisüsteemis. G-valkude aktiveerimisel osalevad nii G-valguga seonduvad retseptorid kui ka mitmed rakusisesed valgud, mis mõjutavad G-valkude aktiivsust retseptorist sõltumatult. Näiteks RIC8A, mis toimib G-valkude nukleotiidivahetusfaktorina ja tšaperonina. Imetajates on RIC8A avaldunud nii arenevas kui täiskasvanud närvisüsteemis osaledes tunnetuslike, õppimis- ning tajufunktsioonide kujunemisel.
Käesoleva doktoritöö eesmärgiks oli uurida RIC8A rolli hiire närvisüsteemis ja selle arengus. RIC8A puudumine hiire kesk- ja perifeerse närvisüsteemi rakkudest põhjustab neuro-muskulaarset fenotüüpi, mida iseloomustavad lihaste atrofeerumine, motoorika-, tasakaalu- ja koordinatsiooni häired, tõmblused ning sünnijärgne suremus. Ric8A puudulikel hiirtel esinevad kõrvalekalded suurajukoore arengus (nt rakujagunemiste ja neuraalse migratsiooni häired, ajuvatsakeste laienemine, defektne kortikaalne basaalmembraan) ning südame ja silma arengus. Lisaks katsed RIC8A defitsiitsete rakkudega näitasid, et RIC8A on oluline β1-integriini vahendatud tsütoskeleti organiseerimisel ja rakkude migratsioonil. Kirjeldatud defektid on iseloomulikud kaasasündinud lihasdüstroofiatele (Fukuyama lihasdüstroofia, Walker-Warburgi sündroom ja lihase-silma-aju haigus). Seega, häired RIC8A funktsioonis koostöös G-valkude ja β1-integriinide vahendatud signalisatsiooniga võib olla seotud nende haiguste kujunemisel
Correct functioning of central- and peripheral nervous system is essential for normal functioning of the body. Therefore, it is fundamental to control the spatio-temporal development of neural precursor cell division into neurons and their final positioning where they can form functional network between each other. These processes are coordinated by different signalling pathways, where the G-protein mediated signal transduction is one of the prominent mechanism in cell signalling cascade. The activation of G proteins are accomplished via transmembrane G protein coupled receptors or via accessory proteins that influence G proteins receptor-independently. For example, RIC8A affects G protein activity as a guanine nucleotide exchange factor or as a chaperone. In mammals, RIC8A is expressed in the development of the nervous system and plays a role in the regulation of behavior, memory and learning in adults. Current thesis is focused on the role of RIC8A in the nervous system and its development. Ablation of RIC8A in central- and peripheral nervous system causes defects in neuromuscular signalling which is manifested by muscle atrophy and impairment of movements, occasional tremors and lethality after birth. Ric8A deficient mice also display malformations in the development of the cerebral cortex (e.g defects in cell division and cell migration, which affect cortical size and lamination, enlargement of the ventricles and defects in the integrity of cortical basement membrane) and in heart and eye development. In addition, studies on the RIC8A deficient cells showed that RIC8A is crucial for the β1-integrin mediated organisation of cytoskeleton and cell migration. These defects are characteristic to the congenital muscular dystrophies (Fukuyama congenital muscular dystropy, Walker Warbur g syndrome and Muscle-Eye-Brain disease) and that defects in RIC8A functioning in concert with G-protein and β1-integrin mediated signalling may be the cause of these diseases.
Correct functioning of central- and peripheral nervous system is essential for normal functioning of the body. Therefore, it is fundamental to control the spatio-temporal development of neural precursor cell division into neurons and their final positioning where they can form functional network between each other. These processes are coordinated by different signalling pathways, where the G-protein mediated signal transduction is one of the prominent mechanism in cell signalling cascade. The activation of G proteins are accomplished via transmembrane G protein coupled receptors or via accessory proteins that influence G proteins receptor-independently. For example, RIC8A affects G protein activity as a guanine nucleotide exchange factor or as a chaperone. In mammals, RIC8A is expressed in the development of the nervous system and plays a role in the regulation of behavior, memory and learning in adults. Current thesis is focused on the role of RIC8A in the nervous system and its development. Ablation of RIC8A in central- and peripheral nervous system causes defects in neuromuscular signalling which is manifested by muscle atrophy and impairment of movements, occasional tremors and lethality after birth. Ric8A deficient mice also display malformations in the development of the cerebral cortex (e.g defects in cell division and cell migration, which affect cortical size and lamination, enlargement of the ventricles and defects in the integrity of cortical basement membrane) and in heart and eye development. In addition, studies on the RIC8A deficient cells showed that RIC8A is crucial for the β1-integrin mediated organisation of cytoskeleton and cell migration. These defects are characteristic to the congenital muscular dystrophies (Fukuyama congenital muscular dystropy, Walker Warbur g syndrome and Muscle-Eye-Brain disease) and that defects in RIC8A functioning in concert with G-protein and β1-integrin mediated signalling may be the cause of these diseases.
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Keywords
närvisüsteemi areng, neurogenees, G-valgud, signaali transduktsioon, guaniin, nukleotiidid, regulatsioon (biol.), talitlushäired, transgeensed loomad, loomkatsed, development of nervous system, neurogenesis, G-proteins, signal transduction, guanine, nucleotides, regulation (biol.), functional disorders, transgenic animals, animal experiments