Faculty Profile

John Klingensmith, Ph.D. (Genetics, Harvard University) Associate Professor, Department of Cell Biology Duke University Program in Genetics; Cell and Molecular Biology Program; Developmental Biology Training Program	My lab is interested in how the mammalian body plan is generated during early pregnancy. We seek to understand the mechanisms that establish and pattern the body axes and organ precursors of the embryo. We are using the unique genetic technologies available in the mouse to study induction, pattern formation, and morphogenesis, particularly of the neural tube and head. One approach underway is the targeted mutation or misexpression of cell-signaling genes likely to control these events. Many of these genes function analogously in the development of other organisms, allowing us to exploit the experimental strengths of other model systems to devise better mouse experiments. We also use embryonic tissues from existing mutant and transgenic mice in embryological experiments to probe the roles of cellular interactions in tissue development. Our studies bear on normal mammalian embryogenesis and on its anomalies. Craniofacial and neural tube malformations together account for the majority of serious human birth defects; a key objective of our research is to elucidate the mechanisms by which these problems occur. Projects underway focus primarily on the role of molecules initially identified as important embryonic "organizer" genes. These are genes thought to encode the activities of Spemann's organizer, which is a small group of cells believed to be the source of the signals which induce and pattern many of the primary tissues of the vertebrate embryo. For example, the organizer is presumed to induce neural tissue from naïve ectoderm and to confer anterior to posterior pattern within it. Surprisingly, we have found that mutant mouse embryos lacking the organizer nevertheless develop a neural tube with correct anterior-posterior patterning. Moreover, when we delete the gene encoding a presumed organizer neural-inducing signal, we see no effect on neural development, but rather abnormalities in the head and neck of newborns. Deletion of the known neural-inducing signals simultaneously results in embryos with normal neural induction, though subsequent inductive events are disrupted. Our results show that mammalian neural induction and head initiation are more complex than models based on lower vertebrates suggest, and imply the existence of other means of neural induction and patterning. We are pursuing several complementary strategies to reveal the molecular and cellular bases for these phenomena. Meanwhile, we find that these organizer genes have essential roles in development of specific organs and structures arising later in embryogenesis, including the forebrain, the face, the heart, and several other critical organs. We have obtained phenotypes in our various mutant combinations that very closely resemble two severe human malformation syndromes. Because of the excellent embryological tools available in the mouse, we are now able to address the cellular and molecular defects underlying these birth defects. We are collaborating with clinical geneticists to assess whether mutations in these genes are present in affected patients, which would suggest that the genetic lesion led to the birth defect. Our ongoing work on early axial patterning has thus led us into clinically-relevant research on the etiology of important congenital malformations.

E-mail kling@cellbio.duke.edu 4027 GSRBII Bldg., Box 3709 Duke University Medical Center Durham, NC 27710 Telephone 919-684-9402 (office) 919-684-9405 (lab Fax 919-668-3467

Selected Publications
Miura S, Davis, S, Klingensmith, J and Mishina Y. (2006). BMP signaling in the epiblast is required for proper recruitment of the prospective paraxial mesoderm and development of the somites. Development (in press)

Ravanelli, A. and Klingensmith, J. (2006). "Craniofacial Development" in Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism. ASBMR Publications.

Ilagan, R., Abu-Issa, R., Brown, D. Yang, Y.P., Jiao, K., Schwartz, R., Klingensmith, J. and Meyers, E. (2006). Fgf8 is required for anterior heart field development. Development 133: 2435-2445.

Que, J, Ziel, JW, Choi, M, Klingensmith, J. and Hogan, BL. (2006). Morphogenesis of the mammalian trachea and esophagus: new roles for Noggin and BMP. Differentiation 74: 422-37

Anderson, R.M., Stottmann, R.W., Choi, M., and Klingensmith, J. (2006). Endogenous BMP antagonists regulate mammalian neural crest generation and survival. Developmental Dynamics 235: 2507-2520

Yang, YP and Klingensmith, J. (2006). Roles of organizer factors and BMP antagonism in mammalian forebrain establishment. Developmental Biology 296: 458-75

Stottmann, R.W, Berrong, M., Matta, K., Choi, M and Klingensmith, J. (2006). The BMP antagonist Noggin promotes cranial and spinal neurulation by distinct mechanisms. Developmental Biology 295: 647-63

Davis, S., Miura, S, Hill, C, Mishina, Y, and Klingensmith, J. (2004). BMP Receptor IA is required in the mammalian embryo for endodermal morphogenesis and ectodermal patterning. Developmental Biology 270, 47-63. -PDF-

Petryk, A., Anderson, RM, Jarcho, MP, Leaf, I, Carlson, CS, Klingensmith, J, Shawlot, W, and O'Connor, MB. (2004). Agnathia-holoprosencephaly in mice
deficient for the BMP modulator Twisted Gastrulation. Developmental Biology
267, 374-386. -PDF-

Stottmann, R.W., Choi, M., Mishina, Y., Meyers, E. and Klingensmith, J. (2004). BMP Receptor IA is required in mammalian neural crest cells for development of the cardiac outflow tract and ventricular myocardium. Development 131, 2205-2218. -PDF-

Anderson, R.M., Lawrence, AR, Stottmann, R.W., Bachiller, D. and Klingensmith, J. (2002). Chordin and Noggin promote organizing centers of forebrain development in the mouse. Development (in press).

Bauer KA, George TM, Enterline DS, Stottman RW, Melvin EC, Siegel D, Samal S, Hauser MA, Klingensmith J, Nye JS, Speer MC, the NTD Collaborative Group (2002). A mutation in the gene encoding Noggin is not causative in human neural tube defects, Neurogenetics, (in press).

Stottmann, R.W., Anderson, R.M. and Klingensmith, J. (2001). The BMP antagonists Chordin and Noggin have essential but redundant roles in mouse mandibular outgrowth. Developmental Biology 240, 457-473.

Bachiller, D., Klingensmith, J., Kemp, C., Belo, J. Anderson, R.M., May, S.R., McMahon, A.P., Harland, R.M., Rossant, J. and De Robertis, E.M. (2000). The organizer secreted factors Chordin and Noggin are required for forebrain development in the mouse. Nature 403, 658-661.

Klingensmith, J., Ang, S.L., Bachiller, D., and Rossant, J. (1999). Neural induction and axial patterning in the absence of the node and its derivatives. Developmental Biology 216, 535-549.

Klingensmith, J., Yang, Y., Axelrod, J., Beier, D., Perrimon, N., and Sussman, D. (1996). Conservation of dishevelled structure and function between flies and mice: isolation and characterization of Dvl-2. Mechanisms of Development 58, 15-26.

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