title: STARS is essential to maintain cardiac development and function in vivo via a SRF pathway.
abstract: BACKGROUND
  STARS (STriated muscle Activator of Rho Signaling) is a sarcomeric protein expressed early in cardiac development that acts as an acute stress sensor for pathological remodeling. However the role of STARS in cardiac development and function is incompletely understood. Here, we investigated the role of STARS in heart development and function in the zebrafish model and in vitro.
  
  
  RESULTS
  Expression of zebrafish STARS (zSTARS) first occurs in the somites by the 16 somite stage [17 hours post fertilization (hpf)]. zSTARS is expressed in both chambers of the heart by 48 hpf, and also in the developing brain, jaw structures and pectoral fins. Morpholino-induced knockdown of zSTARS alters atrial and ventricular dimensions and decreases ventricular fractional shortening (measured by high-speed video microscopy), with pericardial edema and decreased or absent circulation [abnormal cardiac phenotypes in 126/164 (77%) of morpholino-injected embryos vs. 0/152 (0%) of control morpholino embryos]. Co-injection of zsrf (serum response factor) mRNA rescues the cardiac phenotype of zSTARS knockdown, resulting in improved fractional shortening and ventricular end-diastolic dimensions. Ectopic over-expression of STARS in vitro activates the STARS proximal promoter, which contains a conserved SRF site. Chromatin immunoprecipitation demonstrates that SRF binds to this site in vivo and the SRF inhibitor CCG-1423 completely blocks STARS proximal reporter activity in H9c2 cells.
  
  
  CONCLUSIONS
  This study demonstrates for the first time that STARS deficiency severely disrupts cardiac development and function in vivo and revealed a novel STARS-SRF feed-forward autoregulatory loop that could play an essential role in STARS regulation and cardiac function.
authors: Department of Cardiovascular Sciences, Glenfield Hospital, Clinical Sciences Wing, University of Leicester, Leicester, United Kingdom. nc69@le.ac.uk
authors: Nelson W
authors: NW
authors: Chong
authors: Andrea L
authors: AL
authors: Koekemoer
authors: Samir
authors: S
authors: Ounzain
authors: Nilesh J
authors: NJ
authors: Samani
authors: Jordan T
authors: JT
authors: Shin
authors: Stanley Y
authors: SY
authors: Shaw
mesh_terms: D000818:Animals; D002460:Cell Line; D020224:Expressed Sequence Tags; D005786:Gene Expression Regulation; D018507:Gene Expression Regulation, Developmental; D006321:Heart / Q000196:embryology* / Q000502:physiology*; D006352:Heart Ventricles / Q000378:metabolism; D006801:Humans; D051379:Mice; D008840:Microfilament Proteins / Q000378:metabolism*; D023421:Models, Animal; D010641:Phenotype; D011401:Promoter Regions, Genetic; D051381:Rats; D026362:Serum Response Factor / Q000378:metabolism*; D013997:Time Factors; D014157:Transcription Factors / Q000378:metabolism; D015027:Zebrafish; D029961:Zebrafish Proteins / Q000378:metabolism*
chemical_list: C464441:ABRA protein, human; C518897:Abra protein, mouse; C461039:Abra protein, rat; D008840:Microfilament Proteins; D026362:Serum Response Factor; D014157:Transcription Factors; D029961:Zebrafish Proteins; C577357:abraa protein, zebrafish