Overview

    The Krauss lab is interested in regulation of cell adhesion and signal transduction pathways during development and how such processes may go awry in disease. We have focused much of our effort on a small group of complex and multifunctional receptor-like proteins of the Ig superfamily. Cdo and Boc have Ig and FnIII repeats in their ectodomains and long, divergent cytoplasmic tails. Fruit fly orthologs are Ihog and Boi.

    Cdo promotes skeletal myogenesis in vivo and in vitro. Cdo binds in a cis manner (in the plane of the same cell membrane) to the cell-cell adhesion molecule N-cadherin. N-cadherin ligation during myoblast differentiation results in binding of  the Cdo intracellular region to: 1) the p38 MAPK pathway scaffold protein JLP and, via JLP, p38 itself; and 2) Bnip-2, a protein that binds the small GTPase, Cdc42. Bnip-2 and JLP are brought together through mutual interaction with Cdo. The Cdo-Bnip-2 interaction stimulates Cdc42 activity, which in turn promotes p38 activity and cell differentiation (Figure 1). Cdo also binds in a cis manner to the netrin and RGM receptor, neogenin to influence netrin-mediated signaling during myogenesis.

    Cdo and Boc also function as both components and targets of the Hedgehog signaling and feedback network. Cdo and Boc bind directly to Sonic hedgehog (Shh) and promote Shh signaling (Figure 1). Mice lacking Cdo or Boc display tissue-specific loss-of-Shh function phenotypes. Cdo-null animals display holoprosencephaly (HPE). HPE is one of the most common human birth defects and is associated with haploinsufficiency for genes encoding Shh pathway components. Clinical expression of HPE is extremely variable, but it is rarely associated with defects in other Shh-dependent structures, such as the limbs. Mice lacking Cdo display HPE with strain-specific severity and without limb defects (Figure 2), modeling human HPE and implicating silent modifier genes as a cause of variability. Boc-null mice are viable, but removal of Boc from Cdo mutant mice worsens the latter’s HPE phenotype.

    Taking these results together, Cdo and Boc act as components of multiple cell surface protein complexes to influence, within specific contexts, signaling by cadherins, netrins and Shh. A long-term goal is to understand these multiple functions at a detailed mechanistic level and to discern whether higher order cross-regulation exists that may tie these mechanisms together.

 

 

Figure 1. Model for N-cadherin-stimulated p38 activation in myoblasts and for Cdo as a multifunctional coreceptor. Cdo bound in cis to ligated N-cadherin cad exists in a state that permits stable interaction with JLP/p38 and Bnip-2/Cdc42. In contrast, Cdo bound to Shh does not interact stably with these factors, although it permits the Shh signal to be transmitted to Ptch1, activating Hedgehog pathway signaling. Note that, while Shh binds both Cdo and Ptch1, the ternary complex shown is hypothetical.

Figure 2: Cdo mutant mice display variable HPE phenotypes dependent on genetic background. A. Frontal views of the midfacial region of four-week old adult mice of the indicated Cdo genotypes on the 129S6 background. The Cdo-/- animal in the right panel shows microforms of HPE, including a single, central maxillary incisor (arrows) and a dysgenic philtrum (arrowheads). Cdo-/- mice of the 129S6 background show such craniofacial midline phenotypes with ~30% penetrance. B. Whole embryos of the indicated Cdo genotypes on the C57BL/6 background at embryonic day (E) 15.5. The arrows indicate that, while the Cdo+/+ embryo has two nostrils and a normal midface, the Cdo-/- embryo displays a single nostril and hypoplastic midface. C. Sections of E11.5 embryos of the indicated Cdo genotypes on the C57BL/6 background. Note the paired lateral ventricles in the Cdo+/- (control) embryo and the single ventricle in the Cdo-/- embryo. Cdo-/- mice of the C57BL/6 background show the more severe HPE phenotypes shown in B and C with ~80% penetrance.

© 2008 Mount Sinai Medical Center