Hedgehog and Patched in Neural Development and Disease

Abstract

The vertebrate central nervous system is organized into functional units dedicated to specific tasks such as the detection of form and of movement. Understanding the embryogenesis of these patterns is a daunting task, but it has been aided greatly by genetic studies in model organisms such as the fruit fly Drosophila. The strength of this approach is exemplified by the Hedgehog (Hh) signaling system, initially identified in flies and subsequently found to play an essential role in human neural development and disease. Misregulation of Hh signaling in humans is associated with mental retardation and gross neural tube defects such as spina bifida, which is a malformation of the spinal column, and holoprosencephaly, a loss of midline structures in the brain and face (8Belloni E. Muenke M. Roessler E. Traverso G. Siegel-Bartelt J. Frumkin A. Mitchell H.F. Donis-Keller H. Helms C. Hing A. et al.Identification of Sonic Hedgehog as a candidate gene responsible for holoprosencephaly.Nat. Genet. 1996; 14: 353-356Crossref PubMed Google Scholar, 57Hahn H. Wicking C. Zaphiropoulous P.G. Gailani M.R. Shanley S. Chidambaram A. Vorechovsky I. Holmberg E. Unden A.B. Gillies S. et al.Mutations of the human homolog of Drosophila patched in the nevoid basal cell carcinoma syndrome.Cell. 1996; 85 (b): 841-851Abstract Full Text Full Text PDF PubMed Scopus (1187) Google Scholar, 86Johnson R.L. Rothman A.L. Xie J. Goodrich L.V. Bare J.W. Bonifas J.M. Quinn A.G. Myers R.M. Cox D.R. Epstein Jr., E. Scott M.P. Human homolog of patched, a candidate gene for the basal cell nevus syndrome.Science. 1996; 272: 1668-1671Crossref PubMed Google Scholar, 166Roessler E. Belloni E. Gaudenz K. Jay P. Berta P. Scherer S.W. Tsui L.C. Muenke M. Mutations in the human sonic hedgehog gene cause holoprosencephaly.Nat. Genet. 1996; 14: 357-360Crossref PubMed Google Scholar). In adults, the Hh pathway is essential for restraining growth in the nervous system and other tissues; mutations in pathway components lead to a variety of tumors, including basal cell carcinoma, the most common human cancer, and medulloblastoma, a childhood brain tumor (49Gailani M.R. Stahle-Backdahl M. Leffell D.J. Glynn M. Zaphiropoulos P.G. Pressman C. Unden A.B. Dean M. Brash D.E. Bale A.E. Toftgard R. The role of the human homologue of Drosophila patched in sporadic basal cell carcinomas.Nat. Genet. 1996; 14: 78-81Crossref PubMed Scopus (473) Google Scholar, 57Hahn H. Wicking C. Zaphiropoulous P.G. Gailani M.R. Shanley S. Chidambaram A. Vorechovsky I. Holmberg E. Unden A.B. Gillies S. et al.Mutations of the human homolog of Drosophila patched in the nevoid basal cell carcinoma syndrome.Cell. 1996; 85 (b): 841-851Abstract Full Text Full Text PDF PubMed Scopus (1187) Google Scholar, 86Johnson R.L. Rothman A.L. Xie J. Goodrich L.V. Bare J.W. Bonifas J.M. Quinn A.G. Myers R.M. Cox D.R. Epstein Jr., E. Scott M.P. Human homolog of patched, a candidate gene for the basal cell nevus syndrome.Science. 1996; 272: 1668-1671Crossref PubMed Google Scholar, 139Oro A.E. Higgins K.M. Hu Z. Bonifas J.M. Epstein E.H. Scott M.P. Basal cell carcinomas in mice overexpressing Sonic Hedgehog.Science. 1997; 276: 817-821Crossref PubMed Scopus (476) Google Scholar, 148Pietsch T. Waha A. Koch A. Kraus J. Albrecht S. Tonn J. Sorensen N. Berthold F. Henk B. Schmandt N. et al.Medulloblastomas of the desmoplastic variant carry mutations of the human homologue of Drosophila patched.Cancer Res. 1997; 57: 2085-2088PubMed Google Scholar, 159Raffel C. Jenkins R.B. Frederick L. Hebrink D. Alderete B. Fults D.W. James C.D. Sporadic medulloblastomas contain PTCH mutations.Cancer Res. 1997; 57: 842-845PubMed Google Scholar, 195Unden A.B. Zaphiropoulos P.G. Bruce K. Toftgard R. Stahle-Backdahl M. Human patched (PTCH) mRNA is overexpressed consistently in tumor cells of both familial and sporadic basal cell carcinoma.Cancer Res. 1997; 57: 2336-2340PubMed Google Scholar, 204Wolter M. Reifenberger J. Sommer C. Ruzicka T. Reifenberger G. Mutations in the human homologue of the Drosophila segment polarity gene patched (PTCH) in sporadic basal cell carcinomas of the skin and primitive neuroectodermal tumors of the central nervous system.Cancer Res. 1997; 57: 2581-2585PubMed Google Scholar, 205Xie J. Johnson R.L. Zhang X. Bare J.W. Waldman F.M. Cogen P.H. Menon A.G. Warren R.S. Chen L.C. Scott M.P. Epstein Jr., E. Mutations of the PATCHED gene in several types of sporadic extracutaneous tumors.Cancer Res. 1997; 57: 2369-2372PubMed Google Scholar). Understanding Hh signaling may lead to improved treatments for these human disorders. Although "the Hh pathway" is now diagrammed in many textbooks, many questions remain, not least of which is how the Hh signal is sent and received. In this review, we focus on what has been learned about Hh signaling in the nervous system, how regulation of cell fate and cell division are interwoven, and what we now know about the intracellular steps in Hh signal transduction. We begin with an