Neuroanatomical development in the absence of PKC phosphorylation of the myristoylated alanine-rich C-kinase substrate (MARCKS) protein.
The myristoylated alanine-rich C-kinase substrate protein (MARCKS) is a widely expressed target of protein kinase C (PKC) phosphorylation. Disruption of Marcks in mice leads to a number of developmental defects within the central nervous system that are completely prevented by expression of an epitope-tagged wild-type human MARCKS transgene. In the present study, we investigated whether PKC phosphorylation of MARCKS is necessary for normal central nervous system development and postnatal survival. Expression at approximately twice normal levels of a mutant MARCKS protein in which the four PKC phosphorylatable serines were replaced by asparagines did not allow postnatal survival of Marcks(-/-) pups. Nonetheless, the rescued animals exhibited none of the characteristic anatomical defects seen in the brains and retinas of knockout mice, suggesting that PKC phosphorylation of MARCKS is not required for normal central nervous system development. Expression studies showed that transgene expression was limited to the central nervous system, which has implications for the lack of postnatal survival as well as for the pathogenesis of the neuronal ectopia characteristic of MARCKS deficiency. A novel aspect of the MARCKS-deficient phenotype was also noted, absence of the pontine nuclei; this was also largely reversed in Marcks(-/-) animals expressing the mutant transgene. These data raise the possibility of a role for MARCKS in the netrin-regulated process of pontine nuclei formation.
Scarlett
Cameron O
CO
Office of Clinical Research and Laboratory of Signal Transduction, A2-05 National Institute of Environmental Health Sciences, 111 Alexander Drive, Research Triangle Park, NC 27709, USA.
Blackshear
Perry J
PJ
D000818:Animals; D001216:Asparagine / Q000235:genetics; D015153:Blotting, Western; D002460:Cell Line; D002474:Cell-Free System; D002490:Central Nervous System / Q000033:anatomy & histology / Q000196:embryology / Q000378:metabolism*; D005314:Embryonic and Fetal Development; D005260:Female; D005347:Fibroblasts; D018507:Gene Expression Regulation, Developmental; D006388:Hemagglutinins / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D008565:Membrane Proteins; D051379:Mice; D018345:Mice, Knockout; D000076250:Myristoylated Alanine-Rich C Kinase Substrate; D010525:Peripheral Nerves / Q000196:embryology / Q000378:metabolism; D010641:Phenotype; D010766:Phosphorylation; D011233:Precipitin Tests; D011247:Pregnancy; D011493:Protein Kinase C / Q000378:metabolism*; D011506:Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D012160:Retina / Q000196:embryology / Q000378:metabolism; D013379:Substrate Specificity; D014059:Tongue / Q000196:embryology / Q000378:metabolism; D019076:Transgenes / Q000235:genetics
D006388:Hemagglutinins; D047908:Intracellular Signaling Peptides and Proteins; C000619710:MARCKS protein, human; C000619711:Marcks protein, mouse; D008565:Membrane Proteins; D011506:Proteins; D000076250:Myristoylated Alanine-Rich C Kinase Substrate; D001216:Asparagine; D011493:Protein Kinase C