title: Functional analysis of SPECC1L in craniofacial development and oblique facial cleft pathogenesis.
abstract: BACKGROUND
  Oblique facial clefts, also known as Tessier clefts, are severe orofacial clefts, the genetic basis of which is poorly understood. Human genetics studies revealed that disruption in SPECC1L resulted in oblique facial clefts, demonstrating that oblique facial cleft malformation has a genetic basis. An important step toward innovation in treatment of oblique facial clefts would be improved understanding of its genetic pathogenesis. The authors exploit the zebrafish model to elucidate the function of SPECC1L by studying its homolog, specc1lb.
  
  
  METHODS
  Gene and protein expression analysis was carried out by reverse-transcriptase polymerase chain reaction and immunohistochemistry staining. Morpholino knockdown, mRNA rescue, lineage tracing and terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling assays were performed for functional analysis.
  
  
  RESULTS
  Expression of specc1lb was detected in epithelia juxtaposed to chondrocytes. Knockdown of specc1lb resulted in bilateral clefts between median and lateral elements of the ethmoid plate, structures analogous to the frontonasal process and the paired maxillary processes. Lineage tracing analysis revealed that cranial neural crest cells contributing to the frontonasal prominence failed to integrate with the maxillary prominence populations. Cells contributing to lower jaw structures were able to migrate to their destined pharyngeal segment but failed to converge to form mandibular elements.
  
  
  CONCLUSIONS
  These results demonstrate that specc1lb is required for integration of frontonasal and maxillary elements and convergence of mandibular prominences. The authors confirm the role of SPECC1L in orofacial cleft pathogenesis in the first animal model of Tessier cleft, providing morphogenetic insight into the mechanisms of normal craniofacial development and oblique facial cleft pathogenesis.
authors.affiliation: Boston and Cambridge, Mass.; and Vienna, Austria From the Division of Plastic and Reconstructive Surgery and the Center for Regenerative Medicine, Massachusetts General Hospital, Harvard Medical School; the Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna; the Departments of Obstetrics, Gynecology and Reproductive Biology, and Pathology, Brigham and Women's Hospital, Harvard Medical School; and the Program in Medical and Population Genetics, Broad Institute of Harvard and Massachusetts Institute of Technology.
authors.forename: Lisa
authors.initials: L
authors.lastname: Gfrerer
authors.forename: Valeriy
authors.initials: V
authors.lastname: Shubinets
authors.forename: Tatiana
authors.initials: T
authors.lastname: Hoyos
authors.forename: Yawei
authors.initials: Y
authors.lastname: Kong
authors.forename: Christina
authors.initials: C
authors.lastname: Nguyen
authors.forename: Peter
authors.initials: P
authors.lastname: Pietschmann
authors.forename: Cynthia C
authors.initials: CC
authors.lastname: Morton
authors.forename: Richard L
authors.initials: RL
authors.lastname: Maas
authors.forename: Eric C
authors.initials: EC
authors.lastname: Liao
mesh_terms: D000818:Animals; D002972:Cleft Palate / Q000235:genetics*; D003394:Craniofacial Dysostosis / Q000235:genetics*; D004195:Disease Models, Animal; D005124:Eye Abnormalities / Q000235:genetics*; D005147:Facial Bones / Q000254:growth & development*; D006801:Humans; D019767:Maxillofacial Abnormalities / Q000235:genetics*; D010750:Phosphoproteins / Q000235:genetics* / Q000502:physiology; D012886:Skull / Q000254:growth & development*; D015027:Zebrafish / Q000235:genetics; D000096985:Calponins
chemical_list: D010750:Phosphoproteins; C558855:SPECC1L protein, human; D000096985:Calponins