Seminar:Ertugrul M. Ozbudak,Friday, 04 June 2010, FENS 2019, 11:00 | Faculty of Engineering and Natural Sciences

Interlinked cell-to-cell signaling networks regulate vertebrate axis formation and left right asymmetry
Ertugrul M. Ozbudak, Ph.D.
Assistant Professor, Yeshiva University
Albert Einstein College of Medicine, Departments of Genetics
Abstract:
Limited set of signaling pathways are recurrently used to spatiotemporally regulate distinct biological processes during both embryonic development and adult tissue homeostasis. Discovering the gene regulatory networks controlled by each pathway will be a crucial step for deciphering its functional role. To achieve this goal only a limited number of transcriptome studies are carried out in living organisms and all hampered by either lack of temporal or spatial control.
The body axis of the vertebrate species is composed of repetitive vertebrae and associated skeletal muscles which are derived from somite segments that are laid down periodically during embryonic development. This periodic spatial pattern formation is controlled by four signaling pathways: Notch, Fgf, Wnt and Retinoic Acid (RA). Disruption of each pathway causes segmentation and axis defects, and depending on the severity of the disruption, results in congenital scoliosis or embryonic death. So far, only a small set of targets of each signaling pathway is identified.
We took advantage of the external development of zebrafish to temporally perturb each signaling pathway and identified early transcriptional targets in the paraxial mesoderm by spatial microdissection: One third of the total targets are regulated by more than one pathway indicating a striking level of cross-talk among the signaling pathways. RA signaling pathway was demonstrated to have a more hierarchical structure than the FGF, WNT and Notch pathways. Differential expression of the transcription factors along the body axis is directly controlled by signaling pathways. In addition, distinct Mediator, TAF & TFIIH complex subunits were discovered to be differentially regulated by different signaling pathways. Knockdown of a dozen of novel target genes resulted in axis elongation defects and knockdown of six genes caused defects in the establishment of left-right asymmetry. Genes receiving regulatory inputs from multiple pathways are demonstrated to be more sensitive to genetic perturbation; hence, they might function as signaling hubs connecting different pathways.

Friday, 04 June 2010, FENS 2019, 11:00