Discovering genes that affect the cerebellum and may contribute to autism and epilepsy
Development of the cerebral cortex is well studied. Less is known about development of the cerebellum, even though it is home to 80% of all neurons. The cerebellum is known for its functions in motor coordination but it also integrates external sensory information with internal input from the cortex and other areas of the brain.
Cerebellar defects are implicated in autism and epilepsy. However, little evidence is available on the molecular factors that contribute to cerebellar malformations. Most patients with cerebellar defects never receive a genetic diagnosis of their condition. Dr. Aldinger identifies and characterizes genes involved in cerebellar development to determine the molecular mechanisms of defects in this region of the hindbrain.
The cerebellum has a highly conserved structure and function, so it is often investigated using model organisms such as mice, with the findings extrapolated to humans. Dr. Aldinger takes the opposite approach. She applies findings from humans to develop mouse models for conditions with cerebellar underdevelopment such as Dandy-Walker syndrome.
Using exome sequencing of samples from families affected by cerebellar malformations, Dr. Aldinger and colleagues find genes involved in cerebellum development. Many are already implicated in neurological functions. Most, such as AUTS2 and BCL11A, affect both cerebellar and cortex development. Dr. Aldinger is developing transgenic mice with the mutations she discovers as models for human cerebellar malformation and neurodevelopment in general.
Dr. Aldinger also conducts transcriptional profiling of brain samples to determine precisely when and where cerebellar development genes are expressed. Laser-capture microdissection and single-cell analysis allows her to fate map specific neural cell types in the human cerebellum. Dr. Aldinger is interested in research collaborations that apply the tools and techniques used to study the genes and processes of cortex development to learn about the cerebellum.
Stage of Development
- Pre-clinical in vivo
- Collaborative research and development opportunity
- Sponsored research agreement
- Consultation agreement
- Collaborative animal model development
- Aldinger KA, Doherty D. The genetics of cerebellar malformations. Seminars in fetal and neonatal medicine. 2016; 21(5):321-332.
- Plummer JT, Evgrafov OV, Bergman MY, Friez M, Haiman CA, Levitt P, Aldinger KA. Transcriptional regulation of the MET receptor tyrosine kinase gene by MeCP2 and sex-specific expression in autism and Rett syndrome. Translational Psychiatry. 2013; 3:e316.
- Aldinger KA, Lehmann OJ, Hudgins L, Chizhikov VV, Bassuk AG, Ades LC, Krantz ID, Dobyns WB, Millen KJ. FOXC1 is required for normal cerebellar development and is a major contributor to chromosome 6p25.3 Dandy-Walker malformation. Nature Genetics. 2009;41(9):1037-1042.
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