Regulation of Dendritic Growth and Remodeling by Rho, Rac, and Cdc42

Abstract

The acquisition of cell type-specific morphologies is a central feature of neuronal differentiation and has important consequences for nervous system function. To begin to identify the underlying molecular mechanisms, we have explored the role of Rho-related GTPases in the dendritic development of cortical neurons. Expression of dominant negative mutants of Rac or Cdc42, the Rho-inhibitory molecule C3 transferase, or the GTPase-activating protein RhoGAP p190 causes a marked reduction in the number of primary dendrites in nonpyramidal (multipolar) neurons and in the number of basal dendrites in neurons with pyramidal morphologies. Conversely, the expression of constitutively active mutants of Rho, Rac, or Cdc42 leads to an increase in the number of primary and basal dendrites. In cortical cultures, as in vivo, dendritic remodeling leads to an apparent transformation from pyramidal to nonpyramidal morphologies over time. Strikingly, this shift in favor of nonpyramidal morphologies is also inhibited by the expression of dominant negative mutants of Cdc42 and Rac and by RhoGAP p190. These observations indicate that Rho, Rac, and Cdc42 play a central role in dendritic development and suggest that differential activation of Rho-related GTPases may contribute to the generation of morphological diversity in the developing cortex.