title: p130Cas, Crk-associated substrate plays essential roles in liver development by regulating sinusoidal endothelial cell fenestration.
abstract: p130Cas, Crk-associated substrate (Cas), is an adaptor/scaffold protein that plays a central role in actin cytoskeletal reorganization. We previously showed that mice in which Cas was deleted (Cas(-/-)) died in utero because of early cardiovascular maldevelopment. To further investigate the in vivo roles of Cas, we generated mice with a hypomorphic Cas allele lacking the exon 2-derived region (Cas(Deltaex2/Deltaex2)), which encodes Src homology domain 3 (SH3) of Cas. Cas(Deltaex2/Deltaex2) mice again died as embryos, but they particularly showed progressive liver degeneration with hepatocyte apoptosis. Because Cas expression in the liver is preferentially detected in sinusoidal endothelial cells (SECs), the observed hepatocyte apoptosis was most likely ascribable to impaired function of SECs. To address this possibility, we stably introduced a Cas mutant lacking the SH3 domain (Cas DeltaSH3) into an SEC line (NP31). Intriguingly, the introduction of Cas DeltaSH3 induced a loss of fenestrae, the characteristic cell-penetrating pores in SECs that serve as a critical route for supplying oxygen and nutrients to hepatocytes. The disappearance of fenestrae in Cas DeltaSH3-expressing cells was associated with an attenuation of actin stress fiber formation, a marked reduction in tyrosine phosphorylation of Cas, and defective binding of Cas to CrkII.
  
  
  CONCLUSIONS
  Cas plays pivotal roles in liver development through the reorganization of the actin cytoskeleton and formation of fenestrae in SECs.
authors.affiliation: Department of Disease Model, Hiroshima University, Hiroshima, Japan.
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Tazaki
authors.forename: Takaaki
authors.initials: T
authors.lastname: Sasaki
authors.forename: Kenta
authors.initials: K
authors.lastname: Uto
authors.forename: Norimasa
authors.initials: N
authors.lastname: Yamasaki
authors.forename: Satoshi
authors.initials: S
authors.lastname: Tashiro
authors.forename: Ryuichi
authors.initials: R
authors.lastname: Sakai
authors.forename: Minoru
authors.initials: M
authors.lastname: Tanaka
authors.forename: Hideaki
authors.initials: H
authors.lastname: Oda
authors.forename: Zen-Ichiro
authors.initials: Z
authors.lastname: Honda
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Honda
mesh_terms: D000199:Actins / Q000502:physiology; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D002460:Cell Line; D022081:Cell Surface Extensions / Q000502:physiology* / Q000648:ultrastructure; D050719:Crk-Associated Substrate Protein / Q000235:genetics / Q000502:physiology*; D003599:Cytoskeleton / Q000502:physiology / Q000648:ultrastructure; D004727:Endothelium / Q000166:cytology / Q000502:physiology* / Q000648:ultrastructure; D005091:Exons / Q000235:genetics; D005260:Female; D022781:Hepatocytes / Q000166:cytology / Q000502:physiology / Q000648:ultrastructure; D008099:Liver / Q000166:cytology / Q000196:embryology* / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D023421:Models, Animal; D010766:Phosphorylation / Q000502:physiology; D051381:Rats
chemical_list: D000199:Actins; D050719:Crk-Associated Substrate Protein