Development - Role of CDK5 in neuronal development

Role of CDK5 in neuronal development

Cyclin-dependent kinase 5 (CDK5) is a member of the small serine/threonine cyclin-dependent kinase (CDK) family.

One of the important roles of CDK5 is a neuronal development and differentiation. There are several activators of CDK5. Role of Neuronspecific activator, cyclin-dependent kinase 5 regulatory subunit 1 (CDK5R1(p35)) in neuron development and differentiation is most well-known [1].

CDK5R1(p35)/ CDK5 controls axonal transport of organelles and proteins (both axonal and anterograde).

One of the most well-known pathways is the CDK5 regulation of Reelin signaling. Reelin is a large secreted signaling glycoprotein that binds to two members of the Low-density lipoprotein receptor family, the Apolipoprotein E receptor-2 (ApoER2) and the Very-low-density lipoprotein receptor (VLDLR). Reelin-activated ApoER2 and VLDLR activate Disabled-1 (Dab1) [2]. It is believed that Dab1 induces protein-tyrosine kinase Fyn activation and is phosphorylated in return [3]. Then, Fyn-phosphorylated Dab1 activatesPhosphoinositide-3-kinase (PI3K)/ v-akt murine thymoma viral oncogene homolog 1 (AKT)/ Glycogen synthase kinase 3 beta (GSK3 beta) pathway [4]. It is known that GSK3 beta is implicated in the regulation of anterograde axonal transport, possibly via phosphorylation of Microtubule-associated protein tau (Tau (MAPT)) [5]. CDK5R1(p35)/ CDK5 inhibited this pathway via phosphorylation of Dab1 [2], [4].

In addition, it is shown that CDK5R1(p35)/ CDK5 phosphorylates Thiol-activated peptidase (NUDEL). NUDEL, along withPlatelet-activating factor acetylhydrolase, isoform Ib alpha subunit (PAFAH1B1(LIS1)), interacts with Dynein 1, cytoplasmic, heavy chain, and thus regulates axonal retrograde transport [6], [7].

Moreover, it is known that CDK5R1(p35)/ CDK5 may regulate neurofilament transport via phosphorylation of Neurofilament H (NEFH), Neurofilament M (NEFM) and Neurofilament L (NEFL) [8], [9] that all are bound to Dynein/ Dynactin motor complex [10], [11].

It is shown that phosphorylation of the neurofilaments by CDK5R1(p35)/ CDK5 can also regulate neurite outgrowth and axon radial growth [8], [12].

CDK5R1(p35)/ CDK5 regulates formation of dendrites during neuronal development. CDK5R1(p35)/ CDK5 directly phosphorylates Beta-catenin and Delta-catenin at Ser-246. Phosphorylated catenins may interact with Protein NIMA-interacting 1 (Pin1) that inhibits catenin degradation [13]. It leads to stimulation of dendrites formation.

On the other hand, CDK5R1(p35)/ CDK5 phosphorylates the Wiskott-Aldrich syndrome protein (WASP)-family veroroline homologous protein 1 (WASF1(WAVE1)). Phosphorylation of WASF1(WAVE1) inhibits its ability to regulate Arp2/3 complex-dependent Actin polymerization and decrease the number of spines on the mature dendrites [14].

References

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   Fyn tyrosine kinase is a critical regulator of disabled-1 during brain development. Current biology : CB 2003 Jan 8;13(1):9-17
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   Phosphatidylinositol 3-kinase interacts with the adaptor protein Dab1 in response to Reelin signaling and is required for normal cortical lamination. The Journal of biological chemistry 2003 Oct 3;278(40):38772-9
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    Bidirectional translocation of neurofilaments along microtubules mediated in part by dynein/dynactin. Molecular biology of the cell 2000 Oct;11(10):3495-508
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    Phosphorylation of WAVE1 regulates actin polymerization and dendritic spine morphology. Nature 2006 Aug 17;442(7104):814-7