John Klingensmith, Ph.D. (Harvard University)
Associate Professor, Department of Cell Biology
Associate Dean, Graduate School
Director of Graduate Studies,
Developmental and Stem Cell Biology Training Program
4027 GSRBII Bldg., Box 3471
Duke University Medical Center
Durham, NC 27710
Our overall research interest is the regulation of organ development, and using the insights from this research to better understand human disease and to inform future therapeutic strategies. Our experiments address the molecular and cellular mechanisms that generate organs from pluripotent progenitor cells, using genetics and embryology as key approaches. Much of our work centers on the roles of intercellular signaling pathways, particularly Bone Morphogenetic Protein (BMP) and Hedgehog signaling. We primarily use the mouse model system, but use zebrafish, chick and cell culture as complementary tools.
A long-standing focus of the lab is to determine the mechanisms that give rise to normal development of rostral organs, and how defects in those processes cause structural malformations (birth defects). We are interested in the embryological basis of clinically significant disruptions of the head and thorax, including congenital heart defects, craniofacial malformations, foregut anomalies and neural tube defects. Most completed and ongoing projects use mouse models for specific human malformations as an experimental system. Comparing such models to normal mouse embryos allows us to gain a foothold in elucidating the molecular and cellular underpinnings of normal organ development. It further reveals important insight into how normal biology is altered to generate a given malformation or syndrome of malformations. Major efforts are now underway to understand how the trachea, esophagus and larynx form from a single tube – this is an important problem in basic cell biology, as well as in disease-oriented research. Similarly, a current focus of the lab is to understand how cell signaling pathways regulate development of the atria and ventricles of the heart.
A new area of active research in the lab is to use our knowledge of developmental signaling pathways to design and test potential molecular therapies for congenital or acquired disease. For example, we have found that in the embryonic heart, BMP signaling promotes myocardial proliferation, whereas in the injured (ischemic) adult heart, it promotes programmed cell death. With collaborators, we found that if we inhibited BMP signaling by genetic or pharmacological means, we reduced the myocardial damage resulting from an experimentally induced coronary artery blockage. Thus, this work has implications for the design of molecular therapies to limit myocardial damage after a “heart attack”. The mechanistic basis for this effect remains a topic of interest. We are similarly using our insights from the regulation of normal and abnormal development to test molecular therapies for mouse models of specific birth defects.
The main impetus for our work is a desire to understand the amazing processes by which a functional organ emerges from groups of pluripotent cells. A key significance of our efforts is that our work will also help in elucidating the basis of important human disorders, including birth defects and heart disease.
Billmyre KK, Klingensmith J. (2015) Sonic hedgehog from pharyngeal arch 1 epithelium is necessary for early mandibular arch cell survival and later cartilage condensation differentiation. Dev Dyn. 2015 Apr;244(4):564-76.
Billmyre KK, Hutson M, Klingensmith J. (2015) One shall become two: Separation of the esophagus and trachea from the common foregut tube. Dev Dyn. 244(3):277-88.
Matsui M, Klingensmith J. (2014) Multiple tissue-specific requirements for the BMP antagonist Noggin in development of the mammalian craniofacial skeleton. Dev Biol. 15;392(2):168-81.
Fausett SR, Brunet LJ, Klingensmith J (2014) BMP antagonism by Noggin is required in presumptive notochord cells for mammalian foregut morphogenesis. Dev Bio 391(1):111-24
Fausett SR, Kligensmith J (2012) Compartmentalization of the foregut tube: developmental origins of the trachea and esophagus. Wiley Interdiscip Rev Dev Biol. 1(2):184-202
Guo W, ZhangL, Christopher DM, Teng ZQ, Fausett SR, Liu C, George OL, Klingensmith J, Jin P, Zhao X (2011) RNA-binding protein FXR2 regulates adult hippocampal neurogenesis by reducing Noggin expression. Neuron. 70(5):924-38
Stottmann RW, Klingensmith J (2011) Bone morphogenetic protein signaling is required in the dorsal neural folds before neurulation for the induction of spinal neural crest cells and dorsal neurons. Dev Dyn 240(4):755-65
Ravanelli AM, Klingensmith J. (2011). The Actin Nucleator Cordon-bleu is Required for Development of Motile Cilia in Zebrafish. Developmental Biology 350, 101-111.
Yang, YP, Anderson, RM, Klingensmith, J (2010). BMP antagonism protects Nodal signaling in the gastrula to promote the tissue interactions underlying mammalian forebrain and craniofacial patterning. Human Molecular Genetics 19, 3030-42
Pachori AS, Custer L, Hansen D, Clapp S, Kemppa E, Klingensmith J. (2010). Bone morphogenetic protein 4 mediates myocardial ischemic injury through JNK-dependent signaling pathway. J Mol Cell Cardiol. 48, 1255-65