Research Summary
Before joining the group of Dr. Michael Gershon in the then, Department of Anatomy & Cell Biology 20 years ago, my previous research first, at Harvard , and at the Albert Einstein College of Medicine, pertained to studies of the development of the peripheral nervous system (specifically sympathetic and sensory neurons). This work included 1) elucidating the biological actions of several trophic factors (high K+, NGF, TGFalpha, TGFbeta,) important in the development and physiology of the PNS and 2) analyzing the specificity of connections established between defined levels of the spinal cord axis with specific ganglia of the sympathetic chain (SCG and lumbar ganglia) in murine embryonic explant cultures. At Columbia, in collaboration with Drs. Gershon, Taube Rothman, Tuan Pham and others and with the laboratory of Dr. John Kessler at Northwestern, I have focused on elucidating the molecular signals that play a role in the commitment, differentiation, survival and diversification of the neural crest-derived enteric neuronal and glial precursors (ENCDC). More specifically, using both in vitro and in vivo approaches in transgenic mice, we have identified several neurotrophic factors, found within the developing rat and mouse gut, that play essential roles in development of the enteric nervous system (ENS). The factors identified so far are: the soluble form of the alpha subunit of laminin -1, GDNF, NT-3, the neuropoietic cytokines CNTF and LIF. More recently we have elucidated at specific stages of ENS development, the multiple biological actions of the bone morphogenetic proteins (BMPs) that regulate the degree of differentiation of the ENCDC into neurons and into specific subsets, in relationship with their birthdates and second into enteric glia and third of gangliogenesis of the ENS, by regulating the polysialylation of NCAM expressed by the neurons. Moreover ,we have evidence that the BMPs regulate the responsiveness and dependence for survival of the enteric neurons to other neurotrophic factors (i.e. NT_3) or of the glia to gliogenic factors such as GGF-2, by upregulating the transducing receptors (TrkC or ErbB3. At the moment my research focus on the developmental regulation of enteric dopaminergic neurons, that can be affected in Parkinson's Disease models.
Selected Publications
1.
Chalazonitis, A., Rothman, T.P., Chen, J., Lamballe, F., Barbacid, M. and Gershon, M.D. Neurotrophin-3 induces neural crest-derived cells from fetal rat gut to develop in vitro as neurons or glia. The J. Neurosci. 14:6571-6584,
1994.
2.
Chalazonitis, A., Tennyson, V.M., Kibbey, M.C., Rothman, T.P., and Gershon, M.D. The alpha1 Subunit of Laminin-1 Promotes the Development of Neurons by Interacting with LBP110 Expressed by Neural Crest-Derived Cells Immunoselected from the Fetal Mouse Gut. J. Neurobiol. 33:118-138,
1997.
3.
Chalazonitis, A., Rothman, T.P., Chen, J., Vinson, E.N., MaCLennan, A.J. and Gershon, M.D. Promotion of the Development of Enteric neurons and Glia by Neuropoietic Cytokines: Interactions with Neurotrophin-3. Devel. Biol. 198:343-365,
1998.
4.
Chalazonitis, A., Rothman, T.P. Chen, J., and Gershon, M.D. Age-dependent Differences in the Effects of GDNF and NT-3 on the Development of Neurons and Glia from Neural-Crest-Derived Precursors Immunoselected from the Fetal Rat Gut: Expression of GFRalpha1 in vitro and in vivo. Devel. Biol. 204:385-406,
1998.
5.
Chalazonitis, A., Pham,T.D., Rothman T.P., DiStefano P.S., Bothwell M., Blair-Flynn J., Tessarollo, L. and Gershon M.D. Neurotrophin-3 is Required for the Survival-Differentiation of Subsets of Developing Enteric Neurons. The J. Neurosci. 21:5620-5636,
2001.
6.
Chalazonitis, A., DeAutreaux, F., Guha, U., Pham, T.D., Faure, C., Chen, J.J., Roman, D., Kan, L., Rothman, T.P., Kessler, J.A., and Gershon, M.D. Bone Morphogenetic Protein-2 and -4 Limit the Number of Enteric neurons But Promote Development of a TrkC-Expressing Neurotrophin-3-Dependent Subset. The J. of Neurosci. 24:4266-4282,
2004.
7. Faure, C.,
Chalazonitis, A., Rheaume, C., Bouchard, G., Sampathkumar,S-G., Yarema, K., and Gershon,MD. Gangliogenesis in the enteric nervous system: roles of the polysialylation of the neural cell adhesion molecule and its regulation by Bone Morphogenetic Protein-4. Developmental Dynamics 236:44-59,
2007.
8. Nagai, M., Re, D.B. Tetsuya, N.,
Chalazonitis, A., Jessell, T.M., Wichterle, H., and Przedborski, S. Astrocytes expressing ALS-linked mutated SOD1 release factors selectively toxic to motor neurons. Nature Neurosci 10: 615-622,
2007.
9.
Chalazonitis, A., Pham, T.D., Li, Zs., Roman, D., Guha, U., Gomes, W. Kan, L, Kessler J.A., and Gershon, M.D. Bone Morphogenetic Protein Regulation of Enteric Neuronal Phenotypic Diversity: Relationship to Timing of Cell Cycle Exit. The Journal of Comp. Neurol. 509: 474-492,
2008.
10.
Chalazonitis, A., D'Autreaux, F., Pham, TD., Kessler, JA and Gershon, MD. Bone Morphogenetic Proteins regulate enteric gliogenesis by modulating ErbB3 signaling. Devel. Biol. 350: 64-79,
2011.
11.
Chalazonitis, A., Tang, A.A., Shang, Y., Pham, T.D., Hsieh, I., Setlik, W., Gershon, M.D., and Huang, E.J. Homeodomain Interacting Protein Kinase 2 Regulates Postnatal Development of Enteric Dopaminergic Neurons and Glia via BMP Signaling . The J. Neurosci. 31:13746-13757,
2011.
Recent Reviews 1.
Chalazonitis, A., Kessler, J.A. Pleiotropic Effects of the Bone Morphogenetic Proteins on Development of the Enteric Nervous System. Dev Neurobiol: 72: (6) 843-856,
2012. Epub 2011 Dec 29. (doi: 10.1002/dneu.22002).
2.
Chalazonitis, A. Gershon, M.D. and Greene, L.A., Cell Death and the Developing Enteric Nervous System. Neurochem Int. 61: (6) 839-847,
2012. Epub 2012, Feb 8 (doi:10.1016/j.neuint.2012.01.028).
