NR2F1 in neural crest cells: a novel approach to model Bosh-Boonstra-Schaaf Optic Atrophy Syndrome (BBSOAS).

• Applicant: Dr. Magdalena Laugsch, Ph.D.
• Subject Area: Human Genetics
• Term: since 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 450057775

NR2F1 is a transcriptional factor important for cell differentiation and neurogenesis. Mutations or deletions in the NR2F1 gene cause Bosch-Boonstra-Schaaf Optic Atrophy Syndrome (BBSOAS), a rare autosomal dominant disease characterized by a broad range of phenotypes, including delayed development, intellectual disability, optic atrophy, craniofacial abnormalities, cerebral hearing impairment. The dysmorphic facial features are very similar to those associated with human neurocristopathies - congenital abnormalities and syndromes arising from defects in neural crest development. Neural crest is a transient embryonic cell population that gives rise to more than one hundred different cell types, e.g., craniofacial bones, cartilage, inner ear, peripheral nervous system, and secretory cells. Beyond neuronal tissue, NR2F1 is also expressed in human neural crest cells (hNCC), and hence involved in the craniofacial and brain development. NR2F1 depletion downregulates genes essential for proper hNCC and craniofacial development. Consequently, we hypothesize that some of the features observed in BBSOAS, including facial malformation, might arise from hNCC abnormalities caused by aberrant NR2F1 expression. Since BBSOAS, as a neurodevelopmental disorder, has never been investigated in hNCC, we will make a first step in interrogating potential hNCC contribution to BBSOAS. We will employ induced pluripotent stem cells (hiPSC) derived from BBSOAS-patients, and engineered by CRISPR/Cas9, and differentiate them into hNCC. Combining epigenomic, transcriptomic data, and advanced computational analysis will link the physiological differences that arise from different NR2F1 defects and aid dissection of the heterogeneous manifestations of BBSOAS. Our genome-wide results of this pioneering approach will facilitate a better understanding of the genetic basis of BBSOAS and other disorders associated with hNCC and craniofacial abnormalities. Elucidating regulatory networks controlled by NR2F1 during hNCC development and identifying novel genetic variants among them may open up novel research avenues for diagnosis and therapy of BBSOAS and other neurocristopathies. Hence, our study has the unique power to transfer the knowledge gained from a rare disease such as BBSOAS to other common diseases. We anticipate that our multidisciplinary experimental approaches will broaden the current range of techniques and interests at our institute and should serve as a framework for further studies. Considering that the action and regulation of NR2F1 is distinct in different tissues (neural versus neural crest) and controlled by different mechanisms, our experimental approach should be useful to model the pathological relevance of NR2F1 alterations in neuronal lineages. Thus, our results may have far-reaching medical relevance, providing an excellent foundation for further innovative studies.

• DFG Programme: Research Grants