Nedd4l-Mediated Ubiquitination Activity And Akt-Mtor Pathways Deregulation In Malformations Of Cortical Development
Reference : PhD Jamel Chelly - Juliette Godin
Offer publication : Jan. 29, 2018
Jamel CHELLY’s and Juliette GODIN’s team (Co-supervision)
Translational medicine and neurogenetic department
IGBMC, INSERM U964, CNRS/UdS UMR7104
Contact : firstname.lastname@example.org; Chelly@igbmc.fr
The development of the human cerebral cortex requires coordinated spatial and temporal regulation of interdependent developmental processes that include proliferation, migration and layering, as well as differentiation of distinct neuronal populations. Disruption of any of these processes can result in a wide range of developmental disorders. Many of these disorders are classified within the group of malformations of cortical development (MCD), often associated with severe intellectual disability (ID) and epilepsy.
In a recent study, we and others, have shown that missense mutations in the HECT domain of the E3 ubiquitin ligase NEDD4L lead to a MCD called periventricular nodular heterotopia (PNH) (Broix et al, Nature Genetics, 2016). Cellular and expression data showed a sensitivity of PNH-associated mutants to proteasome degradation that contrasts with the stability of WT NEDD4L. Moreover, in utero electroporation approach showed that PNH-related mutants and excess of WT NEDD4L affect neurogenesis and neuronal positioning. Further investigations, including rapamycin based experiments, revealed a differential deregulation of PI3K-AKT-mTOR and TGF-β-Smad2/3 signaling pathways. Excess of WT NEDD4L leads to a disruption of Dab1 and mTORC1 pathways, while PNH-related mutations are associated with a deregulation of mTORC1, AKT and Smad2/3 activities in basal conditions and upon TGF-β activation.
Although, altogether these findings highlight the critical role of NEDD4L in brain development, they also raise several issues that remain to be understood. For instance, how mutations in the HECT domain leading to unstable NEDD4L mutants deregulate PI3K-AKT-mTOR signaling pathways?; what are the mechanisms by which signaling alterations affect the different developmental processes during corticogenesis? What are the substrates and interactors of NEDD4L that are at the basis of the characterized biological disruptions?
In view of these critical findings, questions and hypothesis, and in order to advance our understanding of the function of NEDD4L and NEDD4L-mediated ubiquitinylation role during brain development, the main objective of our proposal will be focused on the dissection and the understanding of the role of NEDD4L in the regulation of AKT/mTOR pathways and its contribution in the regulation of neurodevelopmental processes underlying cortical development. To address these objectives, we set up a collaborative project that brings together groups with complementary skills (Genetics (Chelly’s lab), cortical development (Godin’s lab), ubiquitination (Sumara’s lab)). We will combine investigations of unique conditional knock-in (cKI) mouse model and hiPSC derived from a patient’s fibroblasts bearing the heterozygous p.R897Q mutation (and their isogenic controls that will be generated by CRISPR/Cas9), as well as targeted and large scale in vitro and in vivo studies to:
- Decipher the cellular consequences of NEDD4L mutation during cortical development (AIM1)
- Identify relevant NEDD4L substrates and interactors critical for the regulation the AKT/mTOR pathways during cortical developmental processes (AIM2).
Although the PhD candidate will be in charge of the first aim (under the supervision of J GODIN and J Chelly), he will be associated to the second aim of the project led by the lab of Isabela Sumara at IGBMC.
Application Deadline : Nov. 1, 2018