Cdk5 and Trio modulate endocrine cell exocytosis

Xin, Xiaonan; Ferraro, Francesco; Back, Nathan; Eipper, Betty A.; Mains, Richard E.

doi:10.1242/jcs.01333

Cited by 53 publications

(67 citation statements)

References 63 publications

(71 reference statements)

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“…The relationship between Cdk5 and Rac1 activity has been reported (Nikolic et al, 1998;Xin et al, 2004), and Posh contains several , n=30 cells (three slices); Dcx-shRNA+wt-Dcx, n=20 cells (two slices) in C. Control, DcxshRNA, Dcx-shRNA+wt-Dcx, p27-shRNA and p27-shRNA+wt-p27 kip1 , n=30 cells (three sections) in E. (F) Schematic of the molecular mechanisms of dilation formation and nuclear elongation. Migrating neurons exhibit unique morphological changes: they form a cytoplasmic dilation (1), followed by nuclear elongation (2) and forward movement (3).…”

Section: Discussionmentioning

confidence: 81%

Cdk5 and its substrates, Dcx and p27kip1, regulate cytoplasmic dilation formation and nuclear elongation in migrating neurons

et al. 2014

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Neuronal migration is crucial for development of the mammalian-specific six-layered cerebral cortex. Migrating neurons are known to exhibit distinct features; they form a cytoplasmic dilation, a structure specific to migrating neurons, at the proximal region of the leading process, followed by nuclear elongation and forward movement. However, the molecular mechanisms of dilation formation and nuclear elongation remain unclear. Using ex vivo chemical inhibitor experiments, we show here that rottlerin, which is widely used as a specific inhibitor for PKCδ, suppresses the formation of a cytoplasmic dilation and nuclear elongation in cortical migrating neurons. Although our previous study showed that cortical neuronal migration depends on Jnk, another downstream target of rottlerin, Jnk inhibition disturbs only the nuclear elongation and forward movement, but not the dilation formation. We found that an unconventional cyclin-dependent kinase, Cdk5, is a novel downstream target of rottlerin, and that pharmacological or knockdown-mediated inhibition of Cdk5 suppresses both the dilation formation and nuclear elongation. We also show that Cdk5 inhibition perturbs endocytic trafficking as well as microtubule organization, both of which have been shown to be required for dilation formation. Furthermore, knockdown of Dcx, a Cdk5 substrate involved in microtubule organization and membrane trafficking, or p27 kip1 , another Cdk5 substrate involved in actin and microtubule organization, disturbs the dilation formation and nuclear elongation. These data suggest that Cdk5 and its substrates, Dcx and p27 kip1 , characterize migrating neuronspecific features, cytoplasmic dilation formation and nuclear elongation in the mouse cerebral cortex, possibly through the regulation of microtubule organization and an endocytic pathway.

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Section: Discussionmentioning

confidence: 81%

Cdk5 and its substrates, Dcx and p27kip1, regulate cytoplasmic dilation formation and nuclear elongation in migrating neurons

et al. 2014

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“…Consequently, by regulating the ability of Nb1 to associate with F-actin, Cdk5 may influence the activity and localization of complex signaling networks. Interestingly, in neurons Cdk5 is found complexed with Rac1 (Nikolic et al, 1998) and can affect Rac1 activation by RasGRF2 and Trio (Kesavapany et al, 2004;Xin et al, 2004). The fact that Nb1 influences the levels of Rac1-GTP, whereas Cdk5 can modify the function of Nb1, suggests that a tightly balanced relationship between these molecules accounts for the cytoskeletal changes required for neurite outgrowth and neuronal migration.…”

Section: Discussionmentioning

confidence: 99%

Neurabin-I Is Phosphorylated by Cdk5: Implications for Neuronal Morphogenesis and Cortical Migration

Causeret

Jacobs

Terao

et al. 2007

MBoC

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The correct morphology and migration of neurons, which is essential for the normal development of the nervous system, is enabled by the regulation of their cytoskeletal elements. We reveal that Neurabin-I, a neuronal-specific F-actin-binding protein, has an essential function in the developing forebrain. We show that gain and loss of Neurabin-I expression affect neuronal morphology, neurite outgrowth, and radial migration of differentiating cortical and hippocampal neurons, suggesting that tight regulation of Neurabin-I function is required for normal forebrain development. Importantly, loss of Neurabin-I prevents pyramidal neurons from migrating into the cerebral cortex, indicating its essential role during early stages of corticogenesis. We demonstrate that in neurons Rac1 activation is affected by the expression levels of Neurabin-I. Furthermore, the Cdk5 kinase, a key regulator of neuronal migration and morphology, directly phosphorylates Neurabin-I and controls its association with F-actin. Mutation of the Cdk5 phosphorylation site reduces the phenotypic consequences of Neurabin-I overexpression both in vitro and in vivo, suggesting that Neurabin-I function depends, at least in part, on its phosphorylation status. Together our findings provide new insight into the signaling pathways responsible for controlled changes of the F-actin cytoskeleton that are required for normal development of the forebrain.

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“…Binding of agrin to the MuSK receptor complex, for example, leads to the activation of Rac and Pak (26,37). Because Cdk5 has been shown to phosphorylate Pak and RhoGEF, which could activate Rho activity (38,39), Cdk5 may directly or indirectly impact on the clustering of AChRs. The detailed mechanism underlying the effect of Cdk5 on this aspect of postsynaptic specialization remains to be elucidated.…”

Section: Discussionmentioning

confidence: 99%

Aberrant motor axon projection, acetylcholine receptor clustering, and neurotransmission in cyclin-dependent kinase 5 null mice

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

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Cyclin-dependent kinase (Cdk)5 is a key regulator of neural development. We have previously demonstrated that Cdk5͞p35 are localized to the postsynaptic muscle and are implicated in the regulation of neuregulin͞ErbB signaling in myotube culture. To further elucidate whether Cdk5 activity contributes to neuromuscular junction (NMJ) development in vivo, the NMJ of Cdk5 ؊/؊ mice was examined. Consistent with our previous demonstration that Cdk5 phosphorylates ErbB2͞3 to regulate its tyrosine phosphorylation, we report here that the phosphorylation of ErbB2 and ErbB3 and the ErbB2 kinase activity are reduced in Cdk5-deficient muscle. In addition, Cdk5 ؊/؊ mice also display morphological abnormalities at the NMJ pre-and postsynaptically. Whereas the outgrowth of the main nerve trunk is grossly normal, the intramuscular nerve projections exhibit profuse and anomalous branching patterns in the Cdk5 ؊/؊ embryos. The central band of acetylcholine receptor (AChR) clusters is also wider in Cdk5 ؊/؊ diaphragms, together with the absence of S100 immunoreactivity along the phrenic nerve during late embryonic stages. Moreover, we unexpectedly discovered that the agrin-induced formation of large AChR clusters is significantly increased in primary muscle cultures prepared from Cdk5-null mice and in C2C12 myotubes when Cdk5 activity was suppressed. These abnormalities are accompanied by elevated frequency of miniature endplate potentials in Cdk5-null diaphragm. Taken together, our findings reveal the essential role of Cdk5 in regulating the development of motor axons and neuromuscular synapses in vivo.agrin ͉ Cdk5 ͉ ErbB receptor ͉ neuromuscular junction

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Cdk5 and Trio modulate endocrine cell exocytosis

Cited by 53 publications

References 63 publications

Cdk5 and its substrates, Dcx and p27kip1, regulate cytoplasmic dilation formation and nuclear elongation in migrating neurons

Cdk5 and its substrates, Dcx and p27kip1, regulate cytoplasmic dilation formation and nuclear elongation in migrating neurons

Neurabin-I Is Phosphorylated by Cdk5: Implications for Neuronal Morphogenesis and Cortical Migration

Aberrant motor axon projection, acetylcholine receptor clustering, and neurotransmission in cyclin-dependent kinase 5 null mice

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