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Publication : Transgenic complementation of MARCKS deficiency with a nonmyristoylatable, pseudo-phosphorylated form of MARCKS: evidence for simultaneous positive and dominant-negative effects on central nervous system development.

First Author  Kim HS Year  1998
Journal  Dev Biol Volume  200
Issue  2 Pages  146-57
PubMed ID  9705223 Mgi Jnum  J:49470
Mgi Id  MGI:1277515 Doi  10.1006/dbio.1998.8952
Citation  Kim HS, et al. (1998) Transgenic complementation of MARCKS deficiency with a nonmyristoylatable, pseudo-phosphorylated form of MARCKS: evidence for simultaneous positive and dominant-negative effects on central nervous system development. Dev Biol 200(2):146-57
abstractText  MARCKS is a widely expressed protein kinase C substrate that is essential for normal prenatal development of the central nervous system in mice. MARCKS-deficient mice exhibit universal perinatal mortality and numerous developmental abnormalities of the brain and retina. To determine which domains of the protein were important in complementing these neurodevelopmental anomalies, we have interbred MARCKS knockout mice with transgenic mice expressing an epitope-tagged human MARCKS transgene that can completely correct the MARCKS-deficient phenotype. Previous structure-function studies showed that a nonmyristoylatable form of MARCKS could correct all of the neuroanatomical abnormalities, and resulted in approximately 25% viable pups that grew to adulthood and were fertile. The present experiment attempted a similar complementation strategy in which a nonmyristoylatable, pseudo-phosphorylated form of the protein was used, which has been shown to be almost completely cytosolic in cell expression studies. Surprisingly, this transgene was able to complement almost all of the cerebral anatomical abnormalities characteristic of the knockout mice. However, these mice also exhibited a universal, novel phenotype: profound retinal ectopia, in which retinal tissue was often found in the vitreous humor as well as extraocularly. Retrospective evaluation of the original MARCKS knockout phenotype revealed that this anomaly was present in about 43% of the knockout mice, and was clearly detectable as early as embryonic day 12.5, before retinal cell differentiation begins. These data suggest that a nonmyristoylatable, pseudo-phosphorylated form of MARCKS can complement most if not all cerebral aspects of the MARCKS-deficient phenotype, but that it appears to worsen a retinal phenotype, perhaps by exerting a dominant-negative effect on a coexpressed MARCKS homologue. Copyright 1998 Academic Press.
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