Project Summary/Abstract:
The neocortex is an exclusive structure of the mammalian central nervous system. In humans, the neocortex is
involved in higher-order brain functions such as cognition and language. All projection neurons in the neocortex
are born from a common pool of neural progenitors at the surface of the lateral ventricles of the telencephalon.
Post-mitotic projection neurons must migrate from the proliferative niche to their intended cortical layers in order
to mature and establish functional synaptic contacts. Misregulation of PN migration has devastating
consequences for human health and results in a series of neuronal migration disorders that disrupt neural
circuitry and/or brain morphology, leading to cognition problems, neuropsychiatric disease, epilepsy, and
neuroanatomical malformations. The overarching goal of this project is to define novel molecular mechanisms
that instruct projection neuron migration, migration ending, and settling in their final position in the neocortex.
Recently, we have identified the E3 ubiquitin ligase CRL5 as a key regulator of migration and final positioning of
projection neurons in the cortex. Here, we aim to understand the CRL5-dependent molecular mechanisms that
control pyramidal neuron migration and termination. Our preliminary data indicate that CRL5 regulates the levels
of two crucial phosphoinositide signaling lipids, phosphatidylinositol 4,5-bisphosphate (PIP2) and
phosphatidylinositol 3,4,5-trisphosphate (PIP3) in projection neurons. Our data also suggests that CRL5
regulates PIP2 and PIP3 levels by opposing the activity of the phosphatidylinositol 4-phosphate 5-kinase (PIP5K)
and phosphoinositide 3-kinases (PI3K), which synthesizes PIP2 and PIP3, respectively. Moreover, CRL5 also
controls Ca2+ dynamics by regulating the frequency of Ca2+ events, which are crucial for pyramidal neuron
migration. This proposal aims to address the role of CRL5 during projection neuron migration and cortical
development by answering the following questions:
1) How does CRL5 regulate PIP5K and PI3K activity to control phosphoinositide levels?, 2) Is CRL5 regulating
PIP2 and PIP3 levels to control projection neuron migration?, 3) Does CRL5 participate in Ca2+ dynamics in
projection neurons by controlling Ca2+ channels activity/localization?, and 4) Does CRL5-dependent regulation
of PIP2 and PIP3 levels directly affect Ca2+ dynamics? The successful completion of the project will provide the
first detailed molecular framework of how CRL5 controls projection neuron migration and termination to
orchestrate cortical morphogenesis and identify CRL5 as a novel regulator of phosphoinositides metabolism and
Ca2+ dynamics in the nervous system. Completion of this project will offering potential targets for therapeutic
intervention in neuronal migration disorders.