We propose Drosophila melanogaster as animal model to understand the biological causes of human autosomal recessive primary microcephaly (MCPH). All genes causing primary microcephaly (PM) in humans have Drosophila orthologues. To date, the majority of the MCPH-associated genes encode protein that play important roles in different aspect of cell division process, from centrosome biology to kinetochore structure to MT dynamics. Our research project is aimed to clarify the mechanisms underlying impaired neurogenesis in PM by understanding how defects in functionally different proteins impact on the limitation of neural stem cell division capacity. We suggest 2 hypotheses to explain this reduction in neuron number. 1) The genetic defects associated with PM generate high level of DNA damage both/or by affecting the ability to repair spontaneous double strand breaks (DSBs) generated during development and/or by causing chromosome mis-segregation; this genomic instability will ultimately trigger apoptosis leading to production of fewer neurons. 2) Mutations in MCPH-associated genes alter the balance between proliferative and differentiative cell state and induce premature neuron differentiation.
To understand how these biological processes are involved in PM genesis we plan (i) to analyze for both DNA Damage and apoptosis Drosophila mutants of conserved PM genes; (ii) to examine the effect of mutations in additional Drosophila mitotic genes on DNA integrity and cell viability (iii) to study the nuclear architecture by cytological analysis of the distribution of heterochromatic regions.
We believe that our results will shed new light on the genetic and molecular basis of PM.
