Life, death and Sonic hedgehog Joanne M. Britto, David Tannahill, and Roger J. Keynes* Summary The secreted glycoprotein Sonic hedgehog (SHH), a vertebrate homologue of the Drosophila segment polar- ity gene Hedgehog, is essential for the development of diverse tissues during embryogenesis. Studies of SHH function during neural tube and somite development have focused on its role in specifying the dorsoventral polarity of these structures, but a recent report by Ahlgren and Bronner-Fraser (1) supports the possibility that SHH has additional functions in cell survival and cell proliferation. Perturbation of SHH signaling after the early dorsoventral specification of the cranial neural tube leads to increased cell death in both the neural tube and the neural crest. This implies that SHH is continually required as a trophic and/or mitogenic factor during brain development, and expands the variety of cellular responses to SHH signaling. BioEssays 22:499±502, 2000. ß 2000 John Wiley & Sons, Inc. Studies of the vertebrate Sonic hedgehog (Shh) pathway have illuminated our understanding of many developmental processes, particularly the patterning of the neural tube, somites and limb buds. (2±5) The role of Sonic hedgehog (SHH) is now being explored following initial body plan patterning, and a number of reports have uncovered another important function of SHH signaling, namely the regulation of cell survival and proliferation. To appreciate the later roles of SHH, it is first necessary to outline its role in early embryo patterning. SHH and axial patterning Dorsoventral specification of the neural tube results from inductive signals from the underlying notochord and pre- chordal mesoderm (6,7) and this has been attributed to SHH secreted by the notochord. (8,9) SHH is proposed to induce differentiation of the floor plate, and this is achieved by the close association between the presumptive floor plate and the axial notochord. The floor plate subsequently starts to express SHH in response to the notochordal SHH signal. (6) Alternatively, it is possible that, because the floor plate, notochord and dorsal endoderm share a common origin in Hensen's node, all are a source of SHH. (10) After the initial specification phase, SHH is responsible for the further induction of specific classes of motor neurons that develop in an organized array along the ventrolateral portion of the neural tube. (12) The notochord and floor plate also provide signals for the differentiation of the sclerotome in the ventral part of the developing somite. (13) In each case, cells respond to SHH by expressing defined sets of transcription factors that influence cell fate decisions. (3,14) Targeted disruption of Shh in the mouse results in embryonic lethality and a phenotype consistent with defects in the establishment of midline structures. Mutant embryos display cyclopia, holoprosencephaly and an absence of ventral cell types within the neural tube, as well as additional defects in distal limb structures, the vertebral column and most of the ribs. (15) The early embryonic lethality precludes, however, an evaluation of the role of Shh in later embryogenesis and post-natal development. Interestingly, some of the abnormalities in these animals cannot easily be explained solely by defective midline signaling, and this has raised the possibility of additional roles for SHH during development. SHH and cell survival Ahlgren and Bronner-Fraser (1) have now set out to examine the later role of SHH in relation to the loss of branchial arch structures seen in Shh null mice. They blocked SHH function after axial specification by injecting hybridoma cells, secreting an anti-SHH antibody, into the cranial mesenchyme adjacent to the hindbrain of the chick embryo. This method has been shown previously to block SHH signaling effectively in vivo. (16) Immunohistochemical staining after hybridoma cell injection revealed that in the floor plate, notochord and branchial arch endoderm, SHH was bound by the antibody, and, by inference, these tissues were no longer a source of biologically-active SHH. Embryos treated in this way showed a significant reduction in head size one day after the injection, a loss of branchial arch structures after two days, and later craniofacial and brain anomalies similar to those observed in Shh null mice. This is a significant result as it implies separate functions for SHH signaling during midline induction and later devel- opment. The study also reveals a key role for SHH in cell survival, particularly for neural crest cells migrating from the hindbrain. Blocking SHH signaling resulted in a significant increase in programmed cell death (PCD) in the neural tube BioEssays 22:499±502, ß 2000 John Wiley & Sons, Inc. BioEssays 22.6 499 Department of Anatomy, University of Cambridge, UK. Funding agency: The Cambridge Commonwealth Trust. *Correspondence to: Dr. Roger J. Keynes, University of Cambridge, Department of Anatomy, Downing Street, Cambridge, CB2 3DY, UK. E-mail: rjk10@cus.cam.ac.uk What the papers say