The combination of human genetics, animal models and the recent addition of induced pluipotent stem cells (iPSCs) to the human neurodevelopmental disease modeling toolbox has the potential to greatly expand our understanding of human disease mechanisms. To date, a major challenge to understanding human neurodevelopmental disorders has been the lack of affected tissue. The capacity of iPSCs to differentiate the full complement of neural tissue, from neural progentirors (NP) to mature cortical neurons, from patient iPSC opens an exciting new avenue to understanding unique human features of disease. In this application, I propose to tailor this new technology to model defects in neurogenesis which underlie autosomal recessive primary microcephaly (MCPH). MCPH is a neurodevelopmental disorder characterized by a great reduction of head growth in utero and is accompanied by nonprogressive mental retardation. MCPH is the result of cerebral cortex hypoplasia and generalized diminution of an otherwise architecturally normal brain, a phenotype that is thought to result from defective NP proliferation early in development. MCPH is well suited for this new modeling approach as NPs differentiate early in iPSC differentiation protocols and proliferation can be evaluated within the context of neural rosettes. To correlate iPSCs in vitro modeling data to in vivo brain development, I propose to utilize a combination of patient iPSCs, transgenic mouse iPSCs and animal models. To test the sensitivity of iPSC modeling to convey unique mechanistic information, I propose to model two genetic causes for MCPH that should perturb the same set of cells in different ways or with varying severity. To gain a more comprehensive understanding of the role of in neurogenesis in the molecular pathology of MCPH according to the techniques described above I am proposing to model both Nucleoporin 107 (NUP107) and abnormal spindle-like microcephaly associated (ASPM). I recently identified Nucleoporin 107 (NUP107), a gene not previously linked to human disease, as a causative gene for MCPH. To pursue the proposed research, I have generated iPSCs from Nup107 patient and control fibroblasts and chimeric mice for a conditional NUP107 gene trap allele (NUP107GT). I have also identified a novel ASPM mutation, the gene most commonly mutated in MCPH, for which iPSC modeling will be pursued as an independent investigator. The level of mechanistic understanding that can be gained from this modeling approach for MCPH will lay the foundation that can lead to new therapies and insights into how the normal human brain develops.

Public Health Relevance

Primary microcephaly is a neurodevelopmental disorder presumably due to altered neurogenesis and causing a great reduction in brain growth. I have identified a new causative gene, NUP107, and propose to study induced-pluripotent stem cells and knockout mice to model this human disease.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Transition Award (R00)
Project #
5R00HD069624-03
Application #
8677906
Study Section
Special Emphasis Panel (NSS)
Program Officer
Urv, Tiina K
Project Start
2011-09-10
Project End
2016-05-31
Budget Start
2014-06-01
Budget End
2015-05-31
Support Year
3
Fiscal Year
2014
Total Cost
$207,786
Indirect Cost
$55,972
Name
University of Michigan Ann Arbor
Department
Genetics
Type
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109