Title:"Altered mandibular development in Down syndrome linked to modified expression of non-trisomic genes"
Speaker: Dr. Randall Roper, Department of Biology, School of Science, Indiana University-Purdue University Indianapolis
Place: Physics (PHYS) 112; February 2, 2010, Tuesday, 4:30pm


Trisomy 21 results in a range of phenotypes collectively referred to as Down syndrome (DS) including cognitive impairment, craniofacial dysmorphology, and congenital heart defects. Facial dysmorphology is a distinguishing feature found in individuals with DS. The developmental bases for DS phenotypes and the genetic and molecular etiology of how genes in three copies on human chromosome 21 (Hsa21) initiate these phenotypes, including cranial and facial changes, 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 cranium and face including brachycephaly, hypomorphic midface, and small dysmorphic mandible. Quantitative analysis revealed a reduction in the size of the first pharyngeal arch (PA1), the mandibular precursor, at midgestation (embryonic day 9.5 or E9.5) in Ts65Dn as compared to euploid embryos. To characterize how developmental changes lead to the small mandible in trisomic mice, we demonstrate important morphological differences in craniofacial and other precursors in E13.5 trisomic vs. euploid embryos. Our gene expression analysis of the mandibular precursor shows dysregulation of 155 non-trisomic genes including numerous Hox and other homeobox family members. Our research further defines the genetic mechanisms disrupted by trisomy that cause mandibular deficiencies and similar mechanisms may help define other developmental abnormalities associated with DS. The identification of genetic pathways disrupted by trisomy is an important step to propose rational therapies at relevant time points to ameliorate or prevent craniofacial and other DS phenotypes.

Associated Reading:
A neural crest deficit in Down syndrome mice is associated with deficient mitotic response to Sonic hedgehog. Roper RJ, VanHorn JF, Cain CC, Reeves RH. Mech Dev. 2009 Mar-Apr;126(3-4):212-9. Epub 2008 Nov 21.

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