Gender	Male
E-mail	robert.krauss@mssm.edu
Education and Training	Ph.D., University of North Carolina
	Postdoctoral Training, Columbia University
Awards	2006 - 2008 Editorial Board Mol. Cell. Biol.
	2006 - 2008 Editorial Board BMC Cell Division
	2004 - present Editorial Board J Cell Science
	2002 - 2005 Louis and Florence Carp Memorial Foundation Fellow American Heart Association, Heritage Affiliate
	2001 - 2005 Member Cancer Etiology Study Section, NIH
	1999 - 2002 Established Investigator American Heart Association
	1996 - 2000 Irma T. Hirschl Career Scientist
	1993 - 1996 Alexandrine and Alexander L. Sinsheimer Scholar
	1987 - 1990 Individual National Research Service Award National Institutes of Health

Department of Developmental & Regenerative Biology

Krauss Laboratory

Education and Training	Ph.D., University of North Carolina
	Postdoctoral Training, Columbia University

Cell Adhesion and Signal Transduction in Pattern Formation and Cell Differentiation During Development

The Krauss Lab (Summer 2007)

Top row: Jong-Sun Kang, Min Lu, Karen Schachter, Anthony Romer, Dario Sirabella.  Bottom row: Charlotte Petit, Mingi Hong, Ji-Eun Oh, Youn-Joo Yang, Rob Krauss. Not present: Wei Zhang.

The Krauss Laboratory is interested in the mechanisms by which cell-cell contact regulates signal transduction pathways during development, and how such processes may go awry in disease. We have focused much of our effort on skeletal myogenesis, a highly tractable system for addressing questions of signal transduction and morphogenesis. The current major focus of the lab is on a cell surface protein complex found at sites of cell-cell contact and comprised of: a) the related Ig superfamily members Cdo and Boc; b) netrin-3 and its Ig superfamily receptor, neogenin; and c) N- and M-cadherins, along with their associated catenin proteins. These complexes can signal to coordinate multiple aspects of myogenesis, including changes to the transcriptional program and cell morphology that occur during cell differentiation. Recently, we have found that the Cdo intracellular region binds to JLP, a scaffold protein for the p38 MAP kinase pathway, and that this interaction is important for Cdo's promyogenic function. Consistent with these observations, skeletal muscle development in Cdo -/- mice is delayed.

Genetic analysis of Cdo in the mouse has also revealed a role in Sonic Hedgehog (Shh) signaling. Holoprosencephaly (HPE), the most common defect of human forebrain development, 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. In addition to delayed skeletal muscle development, mice lacking Cdo display HPE with strain-specific severity and without limb defects, modeling human HPE and implicating modifier genes as a cause of variability. Shh target gene expression is reduced in the developing forebrains of Cdo-/- mice, and Cdo and Boc function as both components and targets of the Hedgehog signaling and feedback network. Cdo and Boc enhance Shh signaling in multiple ways, including at signal reception (possibly as co-receptors with Patched) and via a parallel mechanism required at the level of Gli transcription factors.

Taking these results together, Cdo and Boc appear to function 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 mechanistic level and to discern whether higher order cross regulation exists that may tie these mechanisms together.

---

Figure 1

Model for a promyogenic cell surface complex.
A complex of cell surface receptors and adhesion molecules found at sites of myoblast cell-cell contact includes Cdo and Boc, which may function as a receptor for a yet-to-be identified ligand. Cdo and Boc interact in cis with N- and M-cadherins, which bind beta- and alpha-catenin. Cdo and Boc also interact with neogenin, a receptor for netrin-3. The intracellular region of Cdo binds to JLP, a scaffold protein for the p38 MAP kinase pathway. Multiple signals emanate from this complex, resulting in activation of promyogenic transcription factors and alteration of the actin cytoskeleton in preparation for fusion.

---

Figure 2

Loss of Cdo results in delayed myogenesis.
Whole mount in situ hybridization of E9.5 wild-type (+/+) and Cdo -/- (-/-) embryos reveals that, while sclerotome development proceeds normally (as visualized with a probe against Pax1), myotomes develop inefficiently (as visualized with a probe against myogenin). Likewise, at E10.5, myogenin-positive cells have infiltrated the developing limb (arrowheads) in the +/+ embryo, but have barely begun to do so in the -/- embryo.

---

Figure 3

Loss of Cdo results in holoprosencephaly (HPE) with strain-specific severity. (Top panels) Cdo-deficient mice (-/-) of the 129/Sv background display facial microsigns of HPE such as solitary central maxillary incisor (arrows) and a dysgenic philtrum (arrowheads) with ~50 percent penetrance. (Bottom panels) In contrast, Cdo-deficient embryos of the C57BL/6 background display severe HPE with ~80 percent penetrance, including a single nostril (arrows on left-hand figures), close-set eyes and hypoplastic midfaces. Most significantly, as shown in the lower right panels, while control +/- embryos show paired lateral ventricles of the forebrain, -/- embryos fail to form an interhemispheric fissure, resulting in a single, centrally-located ventricle.

For more information, please visit the Krauss Laboratory website.

Takaesu G, Kang JS, Bae GU, Krauss RS, Lee CM, Reddy EP, Yi MJ. Activation of p38alpha/beta MAPK in myogenesis via binding of the scaffold protein JLP to the cell surface protein Cdo. J Cell Biol 2006; 175: 383-388.

Tenzen T, Allen BL, Cole F, Kang JS, Krauss RS, Mcmahon AP. The cell surface membrane proteins Cdo and Boc are components and targets of the Hedgehog signaling pathway and feedback network in mice. Dev Cell 2006 May; 10(5): 647-56.

Zhang W, Kang JS, Cole F, Yi MJ, Krauss RS. Cdo functions at multiple points in the Sonic Hedgehog pathway, and Cdo-deficient mice accurately model human holoprosencephaly. Dev Cell 2006 May; 10(5): 657-65.

Zhang W, Yi MJ, Chen X, Cole F, Krauss RS, Kang JS. Cortical thinning and hydrocephalus in mice lacking the immunoglobulin superfamily member CDO. Mol Cell Biol 2006 May; 26(10): 3764-72.

Krauss RS, Cole F, Gaio U, Takaesu G, Zhang W, Kang JS. Close encounters: regulation of vertebrate skeletal myogenesis by cell-cell contact. J Cell Sci 2005 Jun 1; 118(Pt 11): 2355-62.

Cole F, Zhang W, Geyra A, Kang JS, Krauss RS. Positive regulation of myogenic bHLH factors and skeletal muscle development by the cell surface receptor CDO. Dev Cell 2004; 7: 843-854.

Kang JS, Yi MJ, Zhang W, Feinleib JL, Cole F, Krauss RS. Netrins and neogenin promote myotube formation. J Cell Biol 2004; 167: 493-504.

Cole F, Krauss RS. Microform holoprosencephaly in mice that lack the Ig superfamily member CDO. Curr Biol 2003 Mar; 13: 411-415.

Kang JS, Feinleib JL, Knox S, Ketteringham MA, Krauss RS. Pro-myogenic members of the Ig and cadherin families associate to positively regulate differentiation. Proc Natl Acad Sci U S A 2003 Apr; 7(100): 3989-3994.

Kang JS, Mulieri PJ, Hu HY, Taliana L, Krauss RS. BOC, an Ig superfamily member, associates with CDO to positively regulate myogenic differentiation. EMBO J 2002; 21(1&2): 114-124.