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Requirement Of talin1 For Cell Proliferation During Palate And Mandibular Development In Zebrafish
Kana Ishii, MD, Kusumika Mukherjee, PhD, Eric C. Liao, MD, PhD.
Massachusetts General Hospital, Boston, MA, USA.

PURPOSE: The role of cytoskeletal proteins in craniofacial morphogenesis remains understudied. Critical cellular processes like cell morphological change, migration, proliferation and differentiation are coordinated to mediate craniofacial morphogenesis. These cellular processes require extensive interactions between cellular junctions and the extracellular matrix. Adhesion of cells to extracellular matrix is necessary for the development of multicellular organisms both functionally and structurally during embryonic development. The integrin family of cell adhesion molecules regulates interactions between cells and extracellular matrix. Talin (tln), an adaptor protein, is one of the several proteins that link an integrin subunit to the actin filaments. This link is essential to transmit force from the actin cytoskeleton to the extracellular matrix. Gene knockout studies in mice imply that tln1 plays an important role in the early morphogenetic events during embryonic development. However, the role of tln1 in the molecular and cellular mechanisms involved in craniofacial morphogenesis is poorly understood. Given the central role of tln as a cytoskeletal protein that interface with a number of key regulatory pathways, we hypothesize that tln1 is critical in regulating cellular processes that underlie craniofacial morphogenesis. METHODS: The tln1 mutant line was generated from an insertion mutagenesis screen. The expression of tln1 was determined by whole mount in situ hybridization (WISH) during embryogenesis, and the level of expression was analyzed by quantitative and non-quantitative PCR. Craniofacial cartilaginous structures and muscles were examined by Alcian Blue stain and in the mylz2:mCherry transgenic respectively. Cell lineage tracing, morphology characterization, proliferation and apoptosis assays were performed in sox10:kaede and sox10:mCherry transgenic animals.
 RESULTS : The tln1 homozygotes exhibit microcephaly and pericardial edema, and survive until 5 days post fertilization (dpf). WISH analysis shows that tln1 is
expressed in the craniofacial region starting at 48 hours post fertilization (hpf). The mutant is a loss-of-function (LOF) allele demonstrated by quantitative PCR. Analysis of the craniofacial cartilage and muscles show that the lower jaw is shorter and highly malformed, the palate is shorter and the craniofacial muscles are disorganized. There is no observed defect in cranial neural crest cell (CNCC) migration and no increased CNCC death in the mutants. Pulse-chase analyses suggest that defects in directive cell proliferation in the CNCCs may be causing the palate anomalies. Further cell proliferation experiments via EdU and BrDu labeling are ongoing to validate these results. CONCLUSIONS :Tln1 is required for craniofacial development: in formation of the palate, Meckel’s cartilage and a number of other ventral cartilage structures and the craniofacial muscles. We hypothesize that the cytoskeleton and the associated machinery plays a critical role in craniofacial morphogenesis. The analysis of tln1, one of the proteins that link the cytoplasmic domain of integrin to the actin cytoskeleton, will lead to a better understanding of the involvement of the cytoskeletal network in craniofacial dysmorphism.


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