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Objective Canonical Wnt/β-catenin signals play important roles during neuronal differentiation and neurogenesis, but less is known about noncanonical Wnt signals in this context.Recently, increasing evidence demonstrates that noncanonical Wnt/Ca2+ signaling may participate in the neuronal differentiation.Cyclin-dependent kinase 5 (Cdk5) has been previously implicated in the maturation and survival of neurons born during embryonic development.In the present study, the role of noncanonical Wrnt signals and its relationship with Cdk5 activation in neurogenesis and neuronal differentiation is to be explored.Methods The expression and secretion of noncanonical Wnt ligands (Wnt-4, Wnt-5a and Wnt-11) in cortex of different embryonic stages, and RA/BDNF-induced differentiated SH-SY5Y cells were measured by quantitative Real-time PCR (qRT-PCR) and ELISA assays.The Cdk5 activation by Wnt ligands was tested by in vitro kinase assays.The effects of Canonical Wnt/β-catenin/TCF signaling were measured by Top/Fop-Flash reporter assay.Results (1) The expression and secretion of Wnt-4, Wnt-5a and Wnt-11 were all increased in embryonic cortex of different stages and differentiated SH-SY5Y cells.(2) Wnt-5a, but not Wnt-11, can directly activate Cdk5 kinase activity in neuron and is essential in neuronal differentiation.(3) The activation of Cdk5 by Wnt-5a is and not dependent on β3-catenin signals.Conclusion Noncanonical Wnt/Ca2+ signaling may participate in the neurogenesis and neuronal differentiation by activation of Cdk5.