Project: Deciphering the multifaceted pathways underlying MCPH pathogenesis in the mouse and human

Acronym MicroKin
Duration 01/10/2015 - 30/09/2019
Project Topic Microcephaly, i.e. reduction of the head circumference below 3 SD, affects 2% of the overall population and is associated with mental retardation. Despite origin diversity, most likely microcephalies share common pathogenic processes that remain to be identified. To enhance the knowledge in these processes, we will focus on genetic microcephalies (MCPH) that are characterized by a -3 to -13 SD brain size reduction associated with a primary and selective defect in neuron production. The MCPH pathogenic mechanisms will be addressed through very original angles, considering not only centrosome defects in impaired progenitor cell division but also other potential mechanisms such as mitotic catastrophe and energy metabolism imbalance. Our primary objectives are to provide a larger framework of understanding of i) the complex interplay taking place between MCPH genes and other key pathways to maintain proper homeostasis of the progenitor pool necessary for neurogenesis completion; ii) the similarities and differences of progenitor cell behaviour between rodents and humans; iii) the cortical morphogenic defects associated with MPCH. To these aims, we will combine murine genetic approaches (MCPH1-, CDK5RAP2-, ASPM-, Aurora A-, PlK1- conditional knockouts or inducible knockins), pharmacological tools (kinase inhibitors), detailed expression and functional studies in the developing murine and human neocortex, and iPS cells derived from MCPH patients.
Call Neurodevelopmental Disorders

Project partner

Number Name Role Country
1 Inserm Coordinator France
2 Université Libre de Bruxelles Partner Belgium
3 Spanish National Cancer Research Centre Partner Spain
4 Max Planck Institute Partner Germany