Numerous cerebellar malformations have been described in humans. Most cause cognitive, in addition to motor and sensory integration deficits. Surprisingly little is understood regarding the developmental basis of these malformations, particularly since little human specific data is available for normal or abnormal fetal cerebellar development. This proposal seeks to advance knowledge of human cerebellar development and malformations using human fetal samples and mouse models. The human-specific data will directly test the validity of our working mouse-derived hypotheses regarding the causes these disorders and strengthen the foundation of normal developmental data which will inform our ongoing genetic analyses of human cerebellar malformations. We will conduct the first in-depth analysis of normal human fetal cerebellar development from 4-23 Gestational Weeks, covering major developmental events. We will then examine the pathology of human fetal Dandy-Walker malformation the most common human cerebellar malformation, affecting ~1/3000 live births. Mouse models will be generated in conjunction with these experiments to assess the mechanisms of the developmental pathology. Finally, we will generate the first transcriptome data for normal human fetal cerebellar neurons. These cell-type specific data are critically missing from current publicly available brain resources. Our human fetal cerebellar neuron data will be compared to transcriptome data from existing datasets of endogenous mouse developing cerebellar neurons as well as mES and hPSC-derived cerebellar neurons to development to assess their validity as model systems. Further, the data will also be integrated with exome data from human cerebellar malformation patients to facilitate gene discovery for these important and understudied birth defects.

Public Health Relevance

Congenital birth defects of the human cerebellar are common and poorly understood, affecting approximately 1/3000 live births and cause Autism and other intellectual and motor deficits. This proposal examines the cellular and molecular mechanisms that control normal human cerebellar development as well as the abnormal developmental pathology leading to Dandy-Walker malformation, the most common human cerebellar malformation. These studies will enable improved diagnoses and potentially lead to new treatments of these common and often devastating disorders.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Special Emphasis Panel (ZRG1)
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Riddle, Robert D
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Seattle Children's Hospital
United States
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Aruga, Jun; Millen, Kathleen J (2018) ZIC1 Function in Normal Cerebellar Development and Human Developmental Pathology. Adv Exp Med Biol 1046:249-268
Haldipur, Parthiv; Dang, Derek; Millen, Kathleen J (2018) Embryology. Handb Clin Neurol 154:29-44
Haldipur, Parthiv; Dang, Derek; Aldinger, Kimberly A et al. (2017) Phenotypic outcomes in Mouse and Human Foxc1 dependent Dandy-Walker cerebellar malformation suggest shared mechanisms. Elife 6: