David M. Panchision, PhD

---

Training
B.S., 1987 (Biology), College of William and Mary
Ph.D., 1994 (Pharmacology), Medical College of Virginia, Virginia Commonwealth University
Postdoctoral, 1994-2003, NINDS, National Institutes of Health, Laboratory of Dr. Ron McKay

Laboratory Members
Hui-ling Chen, Ph.D.
(Postdoctoral Fellow)

Research Interests
Our interest is in the self-organizing principles that govern the production of stem cells, the generation of cellular diversity and the assembly of tissues. The field of stem cell biology has emerged as a bridge between the traditional fields of cell biology and developmental genetics. Stem cells have certain defining characteristics, including the ability to self-renew extensively and the ability to generate diverse daughter cell types. These cells can therefore be used as tools to study developmentally relevant switches between alternative states, including proliferation versus mitotic arrest, survival versus apoptosis, and multiple fate choices.

Our laboratory uses a defined culture model for assaying the properties and potential of neural stem cells from many ages. These stem cells are easily manipulated and can be efficiently directed to generate multiple cell types and higher order structures. We have also developed vectors that drive the specific and efficient expression of genes in precursor cells of the developing neural tube. These vectors permit a comparative in vivo and invitro analysis of gene function in these cells. Our comparison of results from in vitro and in vivo analysis supports the idea that complex developmental processes can be reproduced and analyzed in vitro using defined methods.

We are interested in how switches in alternative states are coordinated in space and time to generate the cell types and tissue shapes with which we are familiar. We are currently focusing on BMP signaling on neural stem cells as a paradigm to address these questions. These results may have general relevance to other developmentally important signaling pathways and to stem cells from other tissues. Additionally, we are interested in the role that these pathways may have in tissue turnover, regeneration and dysregulation in disease states such as cancer.

A feed-forward mechanism controls dorsal neural precursor production and fate. Bone morphogenetic proteins (BMPs) are secreted ligands that have diverse and sometimes paradoxical effects during embryonic development, including the nervous system. To determine the mechanisms underlying BMP actions, we analyzed the expression of two BMP receptors, BMPR-IA and BMPR-IB, in neural precursor cells in vitro and in vivo. Neural precursor cells always express Bmpr-1a, but Bmpr-1b is not expressed until embryonic day 9 and is restricted to the dorsal neural tube surrounding the source of BMP ligands. We then expressed active and inactive mutant forms of the receptors under the control of pNERV and analyzed their effects in transgenic mice and cultured CNS stem cells. BMPR-IA activation induces (and the ventralizing actions of Sonic hedgehog repressed) expression of Bmpr-1b along with dorsal identity genes in neural stem cells and promotes the proliferation of these dorsalized cells. BMPR-IB activation limited cell numbers by causing mitotic arrest. This results in apoptosis in early gestation embryos and terminal differentiation in mid-gestation embryos. The linked and antagonistic actions of these receptors can be dissociated using loss-of-function receptor mutants. Furthermore, a single BMP ligand can drive this feedforward, self-limiting process in cultured stem cells. Thus, BMP actions on stem cells are first inducing (through BMPR-IA) and then terminating (through BMPR-IB). We speculate that the accumulation of BMPR-IB relative to BMPR-IA in each exposed cell may determine whether cells continue to proliferate or undergo mitotic arrest and differentiate.

BMPs use divergent pathways to generate alternative fates. Stem cells exhibit both age-dependent and density-dependent differences in cell fate in response to BMPs. For example, when fetal forebrain stem cells are grown at low density, BMP treatment results in predominantly myofibroblast generation. At higher densities BMP treatment leads to predominantly Schwann cell generation. While SMAD activation is required for myofibroblast generation, it is not required for Schwann cell generation. Conversely, STAT activation, which is required for instruction to the Schwann cell fate, occurs only at high density in response to BMPs. The serine-threonine kinase FRAP is required for the activation of STAT proteins in response to BMPs. Thus, alternative fates are generated by distinct pathways acting downstream of BMP receptor activation.

Stem Cell Dysfunction in the Etiology of Cancer. Central Nervous System (CNS) tumors are one of the most highly prevalent forms of cancer in the US and are the leading cause of cancer deaths in children. Recent studies provide evidence that cancers can be re-initiated by cells with properties similar to stem cells. These cells comprise a small percentage of the tumor cell population but can reconstitute the phenotypic heterogeneity of the original tumor. This suggests that cancer is caused by stem cell dysfunction. We are investigating the relationship between improper stem cell regulation in the brain and the progression of cancer. This may lead to the development of more selective therapies for the treatment of CNS tumors.

Recent Publications

Kim, J-H., Panchision, D., Kittappa, R., and McKay, R. (2003) Generating CNS neurons from embryonic, fetal and adult stem cells. In Methods Enzymol. Vol 365: 303-327 (PM Wassarman and GM Keller, eds) Academic Press.

*Rajan, P., *Panchision, D.M., Newell, L., and McKay, R.D. (2003). BMP signals alternate through a SMAD or FRAP-STAT pathway to regulate fate choice in CNS stem cells. J. Cell Biology 161:911-921. *Equal contribution.

Panchision, D.M., and McKay, R.D. (2002). The control of neural stem cells by morphogenic signals. Curr. Opin. Genet. Dev. 12:478-487.

Panchision, D.M., Pickel, J.M., Studer, L., Lee, S.H., Turner, P.A., Hazel, T.G., and McKay, R.D. (2001). Sequential actions of BMP receptors control neural precursor production and fate. Genes & Development 15:2094-2110.

Panchision, D.M., Hazel, T.H., and McKay, R.D. (1998). Plasticity and stem cells in the vertebrate nervous system. Curr. Opin. Cell Biol. 10:727-733.

Panchision, D.M., Martin-DeLeon, P.A., Takeshima, T., Johnston, J.M., Shimoda, K., Tsoulfas, P., McKay, R.D., and Commissiong, J.W. (1998). An immortalized, type-1 astrocyte of mesencephalic origin: source of a dopaminergic neurotrophic factor. J. Mol. Neurosci 11:209-221.