CDKL5 and shootin1 interact and concur in regulating neuronal polarization

Mohammad Sarfaraz Nawaz, Elisa Giarda, Francesco Bedogni, Paolo La Montanara, Sara Ricciardi, Dalila Ciceri, Tiziana Alberio, Nicoletta Landsberger, Laura Rusconi, Charlotte Kilstrup-Nielsen

Research output: Contribution to journalArticle

Abstract

In the last years, the X-linked cyclin-dependent kinase-like 5 (CDKL5) gene has been associated with epileptic encephalopathies characterized by the early onset of intractable epilepsy, severe developmental delay, autistic features, and often the development of Rett syndrome-like features. Still, the role of CDKL5 in neuronal functions is not fully understood. By way of a yeast two hybrid screening we identified the interaction of CDKL5 with shootin1, a brain specific protein acting as a determinant of axon formation during neuronal polarization. We found evidence that CDKL5 is involved, at least in part, in regulating neuronal polarization through its interaction with shootin1. Indeed, the two proteins interact in vivo and both are localized in the distal tip of outgrowing axons. By using primary hippocampal neurons as model system we find that adequate CDKL5 levels are required for axon specification. In fact, a significant number of neurons overexpressing CDKL5 is characterized by supernumerary axons, while the silencing of CDKL5 disrupts neuronal polarization. Interestingly, shootin1 phosphorylation is reduced in neurons silenced for CDKL5 suggesting that the kinase affects, directly or indirectly, the post-translational modification of shootin1. Finally, we find that the capacity of CDKL5 to generate surplus axons is attenuated in neurons with reduced shootin1 levels, in agreement with the notion that two proteins act in a common pathway. Altogether, these results point to a role of CDKL5 in the early steps of neuronal differentiation that can be explained, at least in part, by its association with shootin1.

Original languageEnglish
Article numbere0148634
JournalPLoS One
Volume11
Issue number2
DOIs
Publication statusPublished - Feb 1 2016

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

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    Nawaz, M. S., Giarda, E., Bedogni, F., Montanara, P. L., Ricciardi, S., Ciceri, D., Alberio, T., Landsberger, N., Rusconi, L., & Kilstrup-Nielsen, C. (2016). CDKL5 and shootin1 interact and concur in regulating neuronal polarization. PLoS One, 11(2), [e0148634]. https://doi.org/10.1371/journal.pone.0148634