WIDESPREAD NEURONAL ECTOPIA ASSOCIATED WITH SECONDARY DEFECTS IN CEREBROCORTICAL CHONDROITIN SULFATE PROTEOGLYCANS AND BASAL LAMINA IN MARCKS-DEFICIENT MICE

Mice deficient in MARCKS, a prominent neural substrate for protein kin ase C (PKC), die before or shortly after birth. They exhibit high freq uencies of exencephaly, universal agenesis of forebrain commissures, a nd abnormalities of cerebral cortical and retinal lamination, We show here that these mice have widespread and severe neuronal ectopia in th e outer layers of the developing forebrain, manifested by the migratio n of clusters of developing neuroblasts through the basal lamina and o ften through the pial membrane and into the subarachnoid space. This a bnormality became apparent by Embryonic Day (E) 13 or 14, shortly afte r the formation of the early marginal zone. MARCKS deficiency was asso ciated with decreased staining for marginal zone chondroitin sulfate p roteoglycans; this decrease was detectable earlier in development than the neuronal ectopia. Later in development, there was also marked dis ruption of the basal lamina at the pial-glial interface, as evidenced by gross abnormalities in laminin and reticulin staining; however; the basal lamina appeared normal at E9.5. These data indicate that MARCKS is required for the prevention of neuronal ectopia darting developmen t, Potential mechanisms responsible fear the neuronal ectopia in the M ARCKS-deficient mice include decreased expression or increased proteol ytic destruction of basal lamina proteins and marginal zone chondroiti n sulfate proteoglycans in the developing brain. (C) 1997 Academic Pre ss.