Trisomy 21 results in phenotypes collectively referred to as Down syndrome (DS) including facial dysmorphology, a distinguishing feature of individuals with DS. The molecular and genetic etiology of DS phenotypes and how genes in three copies on human chromosome 21 (Hsa21) initiate their development are not well understood. Ts65Dn mice are trisomic for orthologs of about half of the genes found on Hsa21 and exhibit DS-like abnormalities of the skull including brachycephaly, hypomorphic midface, and small dysmorphic mandible. Because many tissues affected in DS, including craniofacial skeleton, have a neural crest (NC) component, it has been hypothesized that trisomy 21 causes a defect in NC. Our preliminary work revealed a paucity of NC and a reduction in the size of the first pharyngeal arch, the mandibular precursor, at midgestation in Ts65Dn as compared to euploid embryos. Additional analyses have demonstrated alterations in generation, migration and proliferation of trisomic NC. It is not known, however, how trisomy initiates genetic and molecular changes causing the NC deficit and ultimately the small mandible in DS. To better understand DS facial dysmorphology, we will perform genetic and molecular analyses at the origin of the trisomic NC deficits. Through cellular and developmental assays, we will determine how attenuation of Dyrk1a in trisomic NC affects NC generation, migration and differentiation. A NC cell culture system will be used to distinguish the intrinsic and extrinsic molecular mechanisms leading to deficits in trisomic NC precursors. RNA microarray analyses at the origin of the NC deficit will be completed to ascertain differential gene expression at the embryonic origin of the trisomic neural crest abnormalities. The proposed research defines the genetic and molecular mechanisms of the NC deficit and is an essential next step to develop effective screening, therapeutic and preventative strategies for craniofacial deficits associated with DS.

Public Health Relevance

To understand the characteristic facial features associated with Down syndrome, it is important to perform genetic and molecular analyses at the origin of the neural crest deficits. Knowledge of how and when trisomic genes affect neural crest provides a basis for effective screening, therapeutic and preventative strategies of craniofacial anomalies associated with Down syndrome.

National Institute of Health (NIH)
National Institute of Dental & Craniofacial Research (NIDCR)
Academic Research Enhancement Awards (AREA) (R15)
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Special Emphasis Panel (ZRG1-MDCN-A (52))
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Scholnick, Steven
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Indiana University-Purdue University at Indianapolis
Schools of Arts and Sciences
United States
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