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Widespread neuronal ectopia associated with secondary defects in cerebrocortical chondroitin sulfate proteoglycans
P J Blackshear1, J Silver, A C Nairn
1Department of Medicine, and the Sarah W. Stedman Center for Nutritional Studies, Duke University Medical Center, Durham, North Carolina 27710, USA.
Abstract:
Mice deficient in MARCKS, a prominent neural substrate for protein kinase C (PKC), die before or shortly after birth. They exhibit high frequencies of exencephaly, universal agenesis of forebrain commissures, and abnormalities of cerebral cortical and retinal lamination. We show here that these mice have wide-spread and severe neuronal ectopia in the outer layers of the developing forebrain, manifested by the migration of clusters of developing neuroblasts through the basal lamina and often through the pial membrane and into the subarachnoid space. This abnormality became apparent by Embryonic Day (E) 13 or 14, shortly after the formation of the early marginal zone. MARCKS deficiency was associated with decreased staining for marginal zone chondroitin sulfate proteoglycans; this decrease was detectable earlier in development than the neuronal ectopia. Later in development, there was also marked disruption 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 during development. Potential mechanisms responsible for the neuronal ectopia in the MARCKS-deficient mice include decreased expression or increased proteolytic destruction of basal lamina proteins and marginal zone chondroitin sulfate proteoglycans in the developing brain.
Insights
Mice lacking MARCKS protein exhibit severe brain developmental defects, including neuronal migration errors. This highlights MARCKS
Area of Science:
- Neuroscience
- Developmental Biology
- Molecular Biology
Background:
- Mice deficient in the myristoylated alanine-rich protein kinase C substrate (MARCKS) protein die perinatally.
- MARCKS is a key substrate for protein kinase C (PKC) and plays a role in neuronal development.
- Previous studies noted high frequencies of exencephaly, agenesis of forebrain commissures, and lamination abnormalities in MARCKS-deficient mice.
Purpose of the Study:
- To investigate the role of MARCKS in preventing neuronal ectopia during forebrain development.
- To elucidate the molecular mechanisms underlying brain abnormalities in MARCKS-deficient mice.
Main Methods:
- Histological analysis of MARCKS-deficient mouse embryos at various developmental stages (E9.5, E13/14).
- Immunohistochemical staining for basal lamina components (laminin, reticulin) and chondroitin sulfate proteoglycans.
- Assessment of neuroblast migration and localization within the developing forebrain.
Main Results:
- MARCKS-deficient mice displayed widespread and severe neuronal ectopia, with neuroblasts migrating through the basal lamina and pial membrane.
- A decrease in marginal zone chondroitin sulfate proteoglycans was observed earlier than neuronal ectopia.
- Significant disruption of the basal lamina at the pial-glial interface, including abnormalities in laminin and reticulin, was noted later in development.
Conclusions:
- MARCKS is essential for preventing neuronal ectopia during brain development.
- Potential mechanisms involve altered expression or degradation of basal lamina proteins and proteoglycans.
- MARCKS plays a critical role in maintaining the structural integrity of the developing brain's extracellular matrix.