Cdk5-mediated JIP1 phosphorylation regulates axonal outgrowth through Notch1 inhibition

Abstract

Background Activated Cdk5 regulates a number of processes during nervous system formation, including neuronal differentiation, growth cone stabilization, and axonal growth. Cdk5 phosphorylates its downstream substrates located in axonal growth cones, where the highly expressed c-Jun N-terminal kinase (JNK)-interacting protein1 (JIP1) has been implicated as another important regulator of axonal growth. In addition, stringent control of the level of intracellular domain of Notch1 (Notch1-IC) plays a regulatory role in axonal outgrowth during neuronal differentiation. However, whether Cdk5-JIP1-Notch1 cooperate to regulate axonal outgrowth, and the mechanism of such joint contribution to this pathway, is presently unknown, and here we explore their potential interaction. Results Our interactome screen identified JIP1 as an interactor of p35, a Cdk5 activator, and we sought to explore the relationship between Cdk5 and JIP1 on the regulation of axonal outgrowth. We demonstrate that JIP1 phosphorylated by Cdk5 at Thr205 enhances axonal outgrowth and a phosphomimic JIP1 rescues the axonal outgrowth defects in JIP1−/− and p35−/− neurons. Axonal outgrowth defects caused by the specific increase of Notch1 in JIP1−/− neurons are rescued by Numb-mediated inhibition of Notch1. Finally, we demonstrate that Cdk5 phosphorylation of JIP1 further amplifies the phosphorylation status of yet another Cdk5 substrate E3-ubiquitin ligase Itch, resulting in increased Notch1 ubiquitination. Conclusions Our findings identify a potentially critical signaling axis involving Cdk5-JIP1-Itch-Notch1, which plays an important role in the regulation of CNS development. Future investigation into the way this pathway integrates with additional pathways regulating axonal growth will further our knowledge of normal central nervous system development and pathological conditions.

Timing dependent neuronal migration is regulated by Cdk5-meidated phosphorylation of JIP1

“…In our previous study, we showed that Cdk5-mediated phosphorylation of JIP1 at Thr 205 promotes neuroaxonal outgrowth (Im et al 2022). Here, we investigated whether Cdk5-mediated phosphorylation of JIP1 at Thr 205 also plays a role in neuronal migration.…”

“…Although JIP1, one of them, has been demonstrated that its phosphorylation by Cdk5/p35 affects the speed of axon growth (Im et al 2022), the outcome of regulating neuronal migration on architecture of cerebral cortex remains to be fully elucidated.…”

Timing dependent neuronal migration is regulated by Cdk5-mediated phosphorylation of JIP1

“…Various molecular players that affect the speed of axon growth have been identified ( Fenlon, 2022 ). Although the JNK-interacting protein 1 (JIP1), one of them, has been demonstrated that its phosphorylation by cyclin-dependent kinase 5(Cdk5)/p35 affects the speed of axon growth ( Im et al, 2022 ), the outcome of regulating neuronal migration on architecture of cerebral cortex remains to be fully elucidated. The mammalian neocortex has a similar structure in rodents and primates, consisting of six layers of neurons that migrate from inner to outer regions during development.…”

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 ).…”