MARCKS DEFICIENCY IN MICE LEADS TO ABNORMAL BRAIN-DEVELOPMENT AND PERINATAL DEATH

The MARCKS protein is a widely distributed cellular substrate for prot ein kinase C. It is a myristoylprotein that binds calmodulin and actin in a manner reversible by protein kinase C-dependent phosphorylation. It is also highly expressed in nervous tissue, particularly during de velopment, To evaluate a possible developmental role for MARCKS, we di srupted its gene in mice by using the techniques of homologous recombi nation. Pups homozygous for the disrupted allele lacked detectable MAR CKS mRNA and protein, All MARCKS-deficient pups died before or within a few hours of birth. Twenty-five percent had exencephaly and 19% had omphalocele (normal frequencies, < 1%), indicating high frequencies of midline defects, particularly in cranial neurulation, Nonexencephalic MARCKS-deficient pups had agenesis of the corpus callosum and other f orebrain commissures, as well as failure of fusion of the cerebral hem ispheres. All MARCKS-deficient pups also displayed characteristic lami nation abnormalities of the cortex and retina. These studies suggest t hat MARCKS plays a vital role in the normal developmental processes of neurulation, hemisphere fusion, forebrain commissure formation, and f ormation of cortical and retinal laminations, We conclude that MARCKS is necessary for normal mouse brain development and postnatal survival .