Characterizing the functions of a microcephaly-related gene in a knock-out mouse model using in vivo MRI, histology and cellular/molecular biology app

Mutations in the human 'Trafficking protein particle complex subunit 9' (TRAPPC9) gene cause microcephaly, intellectual disability, speech impairment and developmental delays. The protein functions in the regulation of intracellular transport and vesicle size. In this project we will use a novel Trappc9 KO line as our preliminary unpublished data confirms microcephaly in young adult mutants through measurements of brain weights as well as brain volumes via high-resolution magnetic resonance imaging (microscopic MRI). We characterised the Trappc9 expression pattern in a subset of neurons and neural progenitor cells (NPCs) of the brain and in neurosphere cultures. We found a reduction in Sox2-positive NPCs in the hippocampal dentate gyrus, but other adult neurogenic regions have not yet been investigated.

Objective 1: Evaluation of abnormalities in Trappc9 deficient brains using MRI and histology, and determination of the developmental onset of microcephaly. Since the developmental onset of microcephaly is unclear, we will undertake a longitudinal in vivo MRI study to examine total brain volumes at various postnatal and juvenile stages.

Objective 2: Functional assessment of neural progenitor cells in vivo and ex vivo, and determination of deficiencies in vesicle transport and sub-cellular compartments in primary neuronal cultures. Ex vivo, we will assess NPC proliferation and differentiation using neurosphere cultures.