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Vol. 18, Issue 4, 1143-1152, April 2007

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Cornichon-like Protein Facilitates Secretion of HB-EGF and Regulates Proper Development of Cranial Nerves

Hideharu Hoshino^*, Tsukasa Uchida^*, Toshiaki Otsuki^*, Shoko Kawamoto, Kousaku Okubo, Masatoshi Takeichi, and Osamu Chisaka^*

*Department of Cell and Developmental Biology, Graduate School of Biostudies, Kyoto University, Kyoto 606-8502, Japan; Research Information Research Division, National Institute of Informatics, Tokyo 101-8430, Japan; Laboratory for Gene Expression Analysis, Center for Information Biology, National Institute of Genetics, Shizuoka 411-8540, Japan; and Laboratory for Cell Adhesion and Tissue Patterning, Center for Developmental Biology, RIKEN, Kobe 650-0047, Japan

Submitted August 24, 2006; Revised December 13, 2006; Accepted January 8, 2007
Monitoring Editor: Marianne Bronner-Fraser

During their migration to the periphery, cranial neural crest cells (NCCs) are repulsed by an ErbB4-dependent cue(s) in the mesenchyme adjoining rhombomeres (r) 3 and 5, which are segmented hindbrain neuromeres. ErbB4 has many ligands, but which ligand functions in the above system has not yet been clearly determined. Here we found that a cornichon-like protein/cornichon homolog 2 (CNIL/CNIH2) gene was expressed in the developing chick r3 and r5. In a cell culture system, its product facilitated the secretion of heparin-binding epidermal growth factor-like growth factor (HB-EGF), one of the ligands of ErbB4. When CNIL function was perturbed in chick embryos by forced expression of a truncated form of CNIL, the distribution of NCCs was affected, which resulted in abnormal nerve fiber connections among the cranial sensory ganglia. Also, knockdown of CNIL or HB-EGF with siRNAs yielded a similar phenotype. This phenotype closely resembled that of ErbB4 knockout mouse embryos. Because HB-EGF was uniformly expressed in the embryonic hindbrain, CNIL seems to confine the site of HB-EGF action to r3 and r5 in concert with ErbB4.

Address correspondence to: Osamu Chisaka (chisaka{at}lif.kyoto-u.ac.jp)