Cdk5 activity is required for Purkinje cell dendritic growth in cell‐autonomous and non‐cell‐autonomous manners

Abstract

Cyclin-dependent kinase 5 (Cdk5) is recognized as a unique member among other Cdks due to its versatile roles in many biochemical processes in the nervous system. The proper development of neuronal dendrites is required for the formation of complex neural networks providing the physiological basis of various neuronal functions. We previously reported that sparse dendrites were observed on cultured Cdk5-null Purkinje cells and Purkinje cells in Wnt1 -mediated Cdk5 conditional knockout (KO) mice. In the present study, we generated L7 -mediated p35; p39 double KO (L7 -p35 ; p39 ) mice whose Cdk5 activity was eliminated specifically in Purkinje cells of the developing cerebellum. Consequently, these mice exhibited defective Purkinje cell migration, motor coordination deficiency and a Purkinje dendritic abnormality similar to what we have observed before, suggesting that dendritic growth of Purkinje cells was cell-autonomous in vivo. We found that mixed and overlay cultures of WT cerebellar cells rescued the dendritic deficits in Cdk5-null Purkinje cells, however, indicating that Purkinje cell dendritic development was also supported by non-cell-autonomous factors. We then again rescued these abnormalities in vitro by applying exogenous brain-derived neurotrophic factor (BDNF). Based on the results from culture experiments, we attempted to rescue the developmental defects of Purkinje cells in L7 -p35 ; p39 mice by using a TrkB agonist. We observed partial rescue of morphological defects of dendritic structures of Purkinje cells. These results suggest that Cdk5 activity is required for Purkinje cell dendritic growth in cell-autonomous and non-cell-autonomous manners. © 2017 Wiley Periodicals, Inc. Develop Neurobiol 77: 1175-1187, 2017.

The Role of CDKs and CDKIs in Murine Development

“…The dosage and activity of Cdk5 is tightly regulated in the brain [ 102 ]; in particular, p35 and p39 are both essential for Cdk5 activity and may be the principal activators of Cdk5 [ 103 ]. Cdk5 is involved in dendritic spine formation, is important in Purkinje cell migration and dendritic growth, and is required for formation of ventral striation; loss of Cdk5 causes GABAergic neuronal death in the developing mouse foetus, as shown in p35 cKO and p39 KO mice [ 104 , 105 , 106 ]. Cdk5 phosphorylation of the neural protein Synapsin III is needed to regulate neurite outgrowth and axonal elongation [ 107 ].…”

The role of Cdk5 in neurological disorders

“…Cyclin-dependent kinase 5 (Cdk5) is a proline-directed serine/threonine kinase, which is a unique component of the family of cyclin-dependent kinases (Dhavan and Tsai, 2001 ; Malumbres, 2014 ). Cdk5 plays a pivotal role in the nervous system, including cortex layer formation, synaptic growth and maturation, synaptic vesicular transport (Liu et al, 2022 ; Takahashi et al, 2022a ), stress-enhanced memory consolidation, dendritic spine formation, neuronal migration and differentiation, neurite outgrowth and length (Chen et al, 2017 ; Huang et al, 2017 ; Shinmyo et al, 2017 ; Lee et al, 2018 ; Nishino et al, 2019 ; Rao et al, 2020 ; Im et al, 2022 ), learning and long-term behavioral changes, axonal regeneration (Xu et al, 2017 ; Hwang and Namgung, 2021 ), brain microtubule network and actin cytoskeleton remodeling (Shah and Lahiri, 2017 ; Shah and Rossie, 2018 ), as well as normal cerebellar development and functions (Lee et al, 2019 ; Li et al, 2019 ; Kodani et al, 2020 ; Ouyang et al, 2020 ). Additionally, Cdk5 also plays a key role in gene expression, cell differentiation, angiogenesis, and aging (Arif, 2012 ).…”