The human brain contains billions of axons that follow precise pathways essential for the establishment of functional connections. Despite intensive efforts, only few disorders resulting from errors in axon guidance have been identified wherein, their molecular etiologies have not been elucidated. I have identified mutations in PCDH12 in families presenting abnormalities in brain connectivity. I now plan to broaden the screening to identify additional novel gene mutations related to brain wiring defects. Identifying genetic causes will not only shed light on the pathological mechanisms but also will provide insight about the cellular and molecular machinery during development. A major challenge for understanding neurodevelopmental disorders to date, has been the lack of affected tissue. The capacity to differentiate neural tissue from patient induced pluripotent stem cells (iPSCs) opens an exciting avenue to reveal unique human features of disease. Thus, during the mentored phase of this award, I propose to utilize a combination of iPSC and animal models to uncover the molecular basis underlying axon guidance and neural circuit formation in the absence of PCDH12. During the independent phase I will conduct mechanistic studies to characterize the functional interaction between PCDH12 and Cofilin pertaining to axon guidance in both iPSC and mouse disease models, utilizing the skills obtained during the mentored phase of the award. To pursue the proposed research, I have generated iPSCs from patient and control fibroblasts and I have started the characterization of Pcdh12-/- mice. My long-term goal is to combine my background in neuronal death and synapse formation with the expertise in axon guidance;which will be acquired during the proposed training, in order to better understand brain wiring defects.
I aim to integrate human genetics, animal, and stem cell disease models to elucidate the molecular mechanisms pertaining to neural circuit formation. I believe that this combination of techniques will provide insights into how the human brain develops and revolutionize our understanding of neurodevelopmental disorders, laying the groundwork for developing new therapies.

Public Health Relevance

This project will explore the function of PCDH12 relevant to neural circuit formation during development and disease, using a combination of human genetics, animal and stem cell disease models. Studies such as these not only uncover basic molecular mechanisms pertinent to human brain development, but also revolutionize our understanding of neurodevelopmental disorders, laying the groundwork for developing new therapies.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Career Transition Award (K99)
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Neurological Sciences Training Initial Review Group (NST)
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Riddle, Robert D
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Rockefeller University
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New York
United States
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Guemez-Gamboa, Alicia; Ça?layan, Ahmet Okay; Stanley, Valentina et al. (2018) Loss of Protocadherin-12 Leads to Diencephalic-Mesencephalic Junction Dysplasia Syndrome. Ann Neurol 84:638-647
Marin-Valencia, Isaac; Gerondopoulos, Andreas; Zaki, Maha S et al. (2017) Homozygous Mutations in TBC1D23 Lead to a Non-degenerative Form of Pontocerebellar Hypoplasia. Am J Hum Genet 101:441-450
Guemez-Gamboa, Alicia; Nguyen, Long N; Yang, Hongbo et al. (2015) Inactivating mutations in MFSD2A, required for omega-3 fatty acid transport in brain, cause a lethal microcephaly syndrome. Nat Genet 47:809-13