The role of progenitors and neurons in the formation of the subcortical band heterotopia: RhoA mutant as mouse model for understanding the molecular and cellular mechanisms underlying this developmental disorder.

• Applicant: Professorin Silvia Cappello, Ph.D.
• Subject Area: Developmental Neurobiology
• Term: from 2013 to 2017
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 240839715

The positioning of neurons in the cerebral cortex is of crucial importance. This is reflected in the serious consequences for patients, in which neurons are not at their normal locations in the cerebral cortex. Such an abnormality is the double-cortex, in which neurons form another band below the cerebral cortex, a second heterotopic cortex. But how the second cortex is generated, was still unclear. Human genetic studies identified mutations in proteins that regulate the cytoskeleton, but whether these proteins have essential functions in neurons themselves, or in the radial glial cells that direct their migration, was not known. I could show in a new mouse model of double-cortex after deletion of the small RhoGTPase RhoA that mainly defects in the cytoskeleton of the radial glial cells are responsible for this. Using transplantation experiments, I showed that RhoA-deficient neurons transplanted in a normal brain (wild type) migrate relatively normally and reach the cortical plate well despite the absence of this important molecule, whereas wild-type neurons when transplanted into the RhoA-deficient cortex during development can not migrate and accumulate into the ectopic double-cortex. This abnormality is due to the formation of an ectopic precursor cell layer and the aberrant process formation of radial glia. In the present application I want to focus on the molecular mechanisms of RhoA: I want to elucidate why RhoA deletion impairs the process formation of radial glial cells significantly more than those of migrating neurons (Project 1a) as well as study the role of RhoA in other types of neuronal migration (tangential migration) (Project 1b). Moreover, I would like to test, using transplantation experiments in other mouse models of double cortex, whether this abnormality is due to defects in radial glia (Project 3). This is an important conceptual question, since the radial glial cells in the human brain have more important functions, due to the folding of the cerebral cortex and the longer distances that have to be bridged. In another project I want to clarify the molecular mechanisms that are underlying the change in the proliferation of progenitor cells after RhoA deletion (Project 2). This is especially exciting because other proteins that regulate the formation of F-actin filaments show similar effects, which would suggest that the regulation of the transcription factor SRF is a common mechanism. By these innovative projects I want to develop new concepts in neuro-developmental biology, such as the regulation of proliferation of neural stem cells via the actin cytoskeleton and clarify the role of the cytoskeleton in radial glial cells in the etiology of neuronal migration disorders.

• DFG Programme: Research Grants