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e investigated the role of the Cdkl3, a mental retardation candidate gene, in neuronal morphogenesis. We show that Cdkl3 mRNA expression is developmentally regulated in the central nervous system, peaking during neonatal stages, and CDKL3 protein is enriched in neuronal nuclei. Downregulating CDKL3 by RNAi decreased dendrite branching, total dendritic length and complexity in cultured cortical neurons, whereas it promoted axon growth without affecting axon/dendrite specification. Furthermore, depleting CDKL3 in developing cortical neurons also inhibited dendritic growth and maturation, and reduced spine density on basal dendrites in vivo. In contrast, overexpressing CDKL3 enhanced dendritic elaboration both in vitro and in vivo and suppressed axonal outgrowth in vitro. Taken together, these findings demonstrate that CDKL3 is involved in neuronal morphogenesis during development.