Kenneth D. Poss, Ph.D.

(Biology, Massachusetts Institute of Technology)

Professor, Cell Biology

Early Career Scientist, Howard Hughes Medical Institute

Regeneration in the zebrafish model system. It has been known for centuries that certain non-mammalian vertebrates, such as urodele amphibians and teleost fish, regenerate complex tissues much more effectively than mammals. Salamanders have long been the central characters employed in vertebrate regeneration studies. Two features make the teleost zebrafish a powerful, complementary model system to study organ regeneration. First, they are highly regenerative, equipped to regrow amputated fins, injured retinae, transected optic nerves and spinal cord, and resected heart muscle. Second, unlike salamanders, they are amenable to both forward and reverse genetic approaches. As is customary with genetic model systems, a wide array of community resources is available for gene discovery and molecular characterization in zebrafish, including mutagenesis screens, transgenesis, microarrays, developmental markers, and genome sequence information.

We are investigating the biology of spectacular regenerative events in zebrafish to discover new cellular mechanisms, and we are also developing new tools to interrogate regeneration deeply at the molecular level. Over the next several years, we will pursue fundamental aspects of organ regeneration—most importantly, how tissue renewal is stimulated by injury, and how newly created cells recognize position and functionally incorporate into existing tissue.

Heart regeneration. There is little or no natural regeneration of the major structural cells of the adult mammalian heart, the cardiomyocytes, after experimental injury paradigms. This regenerative deficiency is highly relevant to human disease, given that the number one cause of morbidity and mortality in the United States is ischemic myocardial infarction and scarring. Several years ago, we found that zebrafish regenerate cardiac muscle after removal of 20 percent of the ventricle, with little or no scarring. This unique model of cardiac injury and regeneration puts us in a great position to address an important question: How are new cardiac cells created and functionally integrated into an injured, contracting, adult heart?

It is a primary goal of our work to define the origin and developmental potential of cellular contributors to regenerated cardiac tissue. Toward this goal, we are developing myriad tools for lineage tracing in zebrafish. These technologies will also advance our field's ability to ask questions about gene function during heart regeneration at high spatiotemporal resolution. For example, we are exploring several fascinating questions regarding how epicardial cells, and generally the non-muscle cells that comprise the cardiac environment, respond to injury and facilitate regeneration. These avenues should yield clues to altering the regenerative capacity of the injured mammalian heart.

Fin regeneration. Zebrafish fins are external, transparent, nonvital, and highly organized structures, making them ideal for asking fundamental, high-resolution questions about complex tissue regeneration. Within two weeks after amputation of the caudal fin, a series of healing, proliferation, and patterning events replaces bone, epidermis, blood vessels, nerves, and connective tissue mesenchyme. We use forward and reverse genetic approaches to identify new regulatory mechanisms critical for appendage regeneration.

A hallmark of limb or fin regeneration is formation of the blastema, a proliferative mass of mesenchymal cells that is maintained as a zone of progenitor tissue for new structures. The central questions are these: (1) What cells give rise to the blastema, and how is its formation activated by injury? (2) How is blastemal activity maintained appropriately throughout regeneration? (3) How is the completion of regeneration remembered and enacted? An obvious strength of the zebrafish model system is the opportunity for mutagenesis screens. In our lab, we are currently screening to identify new regeneration genes, and we have expanded and modified our past approaches to identify greater numbers of interesting mutants.

During appendage regeneration in urodeles and teleosts, tissue replacement is meticulously regulated such that only the appropriate structures are recovered, a phenomenon referred to as positional memory. It is believed that there exists, or is quickly established after amputation, a gradient of positional information along the axes of the appendage that assigns region-specific instructions to injured tissue. We are identifying new candidate genes for maintaining positional memory, and we are using this information to direct reverse genetic approaches that will functionally define new regeneration and homeostasis genes.

Email
K.Poss@cellbio.duke.edu

349 Nanaline Duke Building, Box 3709
Duke University Medical Center
Durham, NC 27710

Telephone 919-681-8457
Fax 919-684-5481


Poss Lab Website

Selected Recent Publications
Gupta, V. and Poss, K. D. (2012).  Clonally dominant cardiomyocytes direct heart morphogenesis.  Nature 484, 479–484. -PDF-

Singh, S. P., Holdway, J. E., and Poss, K. D. (2012).  Regeneration of amputated zebrafish fin rays by de novo osteoblasts. Developmental Cell 22, 879-86. -PDF-

Choi, W. Y. and Poss, K. D. (2012). Cardiac regeneration. Current Topics in Developmental Biology 100, 319-344. -PDF-

Yin, V. P., Lepilina, A., Smith, A., and Poss, K. D. (2012). Regulation of zebrafish heart regeneration by miR-133.  Developmental Biology 365, 319-327. -PDF-

Nachtrab, G., Czerwinski, M., and Poss, K. D.  (2011).  Sexually dimorphic fin regeneration in zebrafish controlled by androgen/GSK3 signaling.  Current Biology 21, 1912-1917. - PDF-

Wang, J., Panáková, D., Kikuchi, K., Holdway, J. E., Gemberling, M., Burris, J. S., Singh, S. P., Dickson, A. L., Lin, Y. F., Sabeh, Werdich, A. A., Yelon, D., MacRae, C. A., and Poss, K. D. (2011). The regenerative capacity of zebrafish reverses cardiac failure caused by genetic cardiomyocyte depletion.  Development 138, 3421-3430. -PDF-

Kikuchi, K., Gupta, V., Wang, J., Holdway, J. E., Wills, A. A., Fang, Y., and Poss, K. D.  (2011).  tcf21+ epicardial cells adopt non-myocardial fates during zebrafish heart development and regeneration.  Development 138, 2895-2902. -PDF-

Kikuchi, K., Holdway, J. E., Major, R. J., Blum, N., Dahn, R. D., Begemann, G., and Poss, K. D.  (2011). Retinoic acid production by endocardium and epicardium is an injury response essential for zebrafish heart regeneration.  Developmental Cell 20, 397-404. -PDF-

Shin, D., Lee, Y., Poss, K. D., and Stainier, D. Y. R.  (2011).  Restriction of hepatic competence by Fgf signaling.  Development 138, 1339-1348. -PDF-

Liu, J., Bressan, M., Hassel, D., Huisken, J., Staudt, D., Kikuchi, K., Poss, K.D., Mikawa, T. and Stainier, D.Y.R. (2010).  A dual role for ErbB2 signaling in cardiac trabeculation.  Development 137, 3867-3875. -PDF-

Poss, K. D. (2010). Advances in understanding tissue regenerative capacity and mechanisms in animals. Nature Reviews Genetics 11, 710-722. -PDF-

Lee, Y., Nachtrab, G., Klinsawat, P. W., Hami, D., and Poss, K. D. (2010). Ras controls melanocyte expansion during zebrafish fin stripe regeneration. Disease Models and Mechanisms 3, 496-503. -PDF-

Yin, C., Kikuchi, K., Hochgreb, T., Poss, K. D., and Stainier, D. Y. R. (2010). Hand2 regulates extracellular matrix remodeling essential for gut-looping morphogenesis in zebrafish. Developmental Cell 18, 973-984. -PDF-

Kikuchi, K., Holdway, J. E., Werdich, A. A., Anderson, R. M., Fang, Y., Egnaczyk, G. F., Evans T., MacRae, C. A., Stainier, D. Y. R., and Poss, K. D. (2010). Primary contribution to zebrafish heart regeneration by gata4+ cardiomyocytes. Nature 464, 601-605. -PDF-

Gonzalez-Quevedo, R., Lee, Y., Poss, K. D., and Wilkinson, D. G. (2010). Neuronal regulation of the spatial patterning of neurogenesis. Developmental Cell 18, 136-147. -PDF-

Lab personnel
Amy Dickson (research tech)
Jennifer Holdway (research tech)
Taylor Wahlig (research tech)
Chen-Hui Chen (postdoctoral fellow)
Wen-Yee Choi (postdoctoral fellow)
Yi Fang (postdoctoral fellow)
Aaron Goldman (postdoctoral fellow)
Junsu Kang (postdoctoral fellow)
Ravi Karra (postdoctoral fellow)
Mayssa Mokalled (postdoctoral fellow)
Jinhu Wang (postdoctoral fellow)
Matt Gemberling (graduate student)
Vikas Gupta (graduate student)
Greg Nachtrab (graduate student)
Sumeet Pal Singh (graduate student)
Valerie Tornini (graduate student)