Sci. STKE, 16 May 2006
DEVELOPMENT Selective Helpers of Hedgehog
Two papers this week demonstrate a critical role for two proteins that bind Hedgehog (Hh) ligands and thereby influence development of the vertebrate nervous system. Tenzen et al. compared transcriptional profiles of embryonic mouse tissues experiencing normal, enhanced, or absent Hh signaling input. They identified two proteins, Cdo (also called Cdon) and Boc, whose expression was decreased in response to Hh signals. Cdo and Boc are membrane proteins related to members of the immunoglobulin superfamily. For the most part, Cdo and Boc were not expressed in regions of the mouse embryo that are regulated by Hh signaling, But this was not always the case, and Cdo was detected in the notochord and at the ventral midline of the neural tube at the time it responded to Hh signals to form the rostral brain and caudal floor plate, whereas Boc was present in the neural tube. The relatively mild defect in brain development seen in Cdo–/– mutants was enhanced in animals heterozygous for sonic hedgehog (Shh, the mouse Hh ligand). Ectopic expression of Boc or Cdo resulted in neural cells adopting a more "ventral" identity than their position in the embryo would normally specify, yet these cells retained normal relative positions to one another, an indication that Cdo- and Boc-mediated cues still depended on intact Hh signals. Additional experiments provided evidence for direct, high-affinity interaction of Boc and Cdo with Shh. These and other results lead the authors to favor a model in which Cdo and Boc bind and sequester Hh molecules, enhancing local H signaling, but possibly also restricting access of Hh to adjacent tissue. Zhang et al. propose that such effects of Cdo are essential for normal brain development. Holoprosencephaly (HPE) is a common abnormality of human brain development that occurs about once in every 250 embryos. The authors observed that Cdo–/– mice show defects in brain development similar to those in human HPE but not defects in the limbs or internal organs. Thus, the Cdo–/– animals show apparent defects in the same subset of Hh-mediated developmental effects as do human subjects with HPE. These animals showed decreased expression of Shh itself and of genes that normally respond to Shh signaling. In cultured cells, Zhang et al. showed that Cdo enhanced transcription of a reporter gene in response to components of the Hh signaling pathway downstream of the receptor (the Smoothened signaling protein or the Gli1 transcription factor), indicating a separate, later point of action in Hh signaling, in addition to its role in interaction with Shh itself. Cdo shows real versatility; it was previously described to promote myogenesis in complexes with immunoglobulin receptors and cadherin adhesion molecules.
T. Tenzen, B. L. Allen, F. Cole, J.-S. Kang, R. S. Krauss, A. P. McMahon, The cell surface membrane proteins Cdo and Boc are components and targets of the hedgehog signaling pathway and feedback network in mice. Dev. Cell 10, 647-656. [PubMed]
W. Zhang J.-S. Kang, F. Cole, M.-J. Yi, R. S. Krauss, Cdo functions at multiple points in the sonic hedgehog pathway, and Cdo-deficient mice accurately model human holoprosencephaly. Dev. Cell 10, 657-665 (2006). [PubMed]
Citation: Selective Helpers of Hedgehog. Sci. STKE 2006, tw160 (2006).
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