The role of the transcription factor Brachyury (Bra) in notochord formation is well documented and evolutionarily conserved throughout the chordate phylum. However, still little is known about the transcription factors controlled directly or indirectly by Bra and about the function of factors acting in concert with Bra in notochord development and evolution. In particular, the knowledge of structure, common features and modalities of regulation of cis-regulatory modules (enhancers) directing expression in the notochord is fragmentary and poor. We have exploited the experimental advantages offered by the ascidian Ciona intestinalis as a model system to isolate and characterize a collection of notochord enhancers from genes that have already been described as Bra targets and from genes whose relationship with Bra is unknown. Our preliminary data, gathered from the comparative analysis of the notochord enhancers, lead us to hypothesize that notochord formation in Ciona relies upon additional, mostly uncharacterized notochord transcription factors that fall into two categories: Bra-downstream factors, controlled directly or indirectly by Bra and acting as its transcriptional intermediaries and factors acting in concert with Bra. We will test these hypotheses through the following specific aims: (1) Isolate minimal regulatory sequences necessary for notochord expression;(2) Identify the activators controlling the minimal enhancer sequences and study their role in notochord development;(3) Identify the enhancers controlling, in turn, selected notochord activators. The broad scope of the proposed research is to rapidly untangle the gene networks underlying the different steps of notochord development and differentiation and to gain valuable insights into the molecular mechanisms controlling gene expression in the notochord during its formation and evolution.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD050704-05
Application #
7771751
Study Section
Genetic Variation and Evolution Study Section (GVE)
Program Officer
Javois, Lorette Claire
Project Start
2006-05-01
Project End
2012-02-28
Budget Start
2010-03-01
Budget End
2012-02-28
Support Year
5
Fiscal Year
2010
Total Cost
$325,153
Indirect Cost
Name
Weill Medical College of Cornell University
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
060217502
City
New York
State
NY
Country
United States
Zip Code
10065
José-Edwards, Diana S; Oda-Ishii, Izumi; Nibu, Yutaka et al. (2013) Tbx2/3 is an essential mediator within the Brachyury gene network during Ciona notochord development. Development 140:2422-33
Katikala, Lavanya; Aihara, Hitoshi; Passamaneck, Yale J et al. (2013) Functional Brachyury binding sites establish a temporal read-out of gene expression in the Ciona notochord. PLoS Biol 11:e1001697
Nibu, Yutaka; Jose-Edwards, Diana S; Di Gregorio, Anna (2013) From notochord formation to hereditary chordoma: the many roles of Brachyury. Biomed Res Int 2013:826435
Aihara, Hitoshi; Katikala, Lavanya; Zeller, Robert W et al. (2013) Optimization of a method for chromatin immunoprecipitation assays in the marine invertebrate chordate Ciona. Mar Biotechnol (NY) 15:520-5
Jose-Edwards, Diana S; Kerner, Pierre; Kugler, Jamie E et al. (2011) The identification of transcription factors expressed in the notochord of Ciona intestinalis adds new potential players to the brachyury gene regulatory network. Dev Dyn 240:1793-805
Kugler, Jamie E; Kerner, Pierre; Bouquet, Jean-Marie et al. (2011) Evolutionary changes in the notochord genetic toolkit: a comparative analysis of notochord genes in the ascidian Ciona and the larvacean Oikopleura. BMC Evol Biol 11:21
Kugler, Jamie E; Gazdoiu, Stefan; Oda-Ishii, Izumi et al. (2010) Temporal regulation of the muscle gene cascade by Macho1 and Tbx6 transcription factors in Ciona intestinalis. J Cell Sci 123:2453-63
Dunn, Matthew P; Di Gregorio, Anna (2009) The evolutionarily conserved leprecan gene: its regulation by Brachyury and its role in the developing Ciona notochord. Dev Biol 328:561-74
Passamaneck, Yale J; Katikala, Lavanya; Perrone, Lorena et al. (2009) Direct activation of a notochord cis-regulatory module by Brachyury and FoxA in the ascidian Ciona intestinalis. Development 136:3679-89
Coric, Tatjana; Passamaneck, Yale J; Zhang, Ping et al. (2008) Simple chordates exhibit a proton-independent function of acid-sensing ion channels. FASEB J 22:1914-23

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