Daniel A. Colón-Ramos, Ph.D.

Phone: (203) 737-3438
Lab: (203) 737-4720
Fax: 203.785-5098
Email: daniel.colon-ramos@yale.edu

Department of Cell Biology
Yale University School of Medicine
BCMM
PO Box 9812
New Haven, CT 06536

<Courier Address>
CNNR Program
Yale University School of Medicine
295 Congress Center, BCMM 436B
New Haven, CT 06510

Colón-Ramos lab: Laboratory of neural circuit development

We are interested in understanding the developmental events that direct precise neural connectivity.  In particular, we are interested in how these events are coordinated in complex neuropil structures such as the brain.  How are these developmental events simultaneously coordinated between pre- and postsynaptic partners to allow precise wiring?  How do they give rise to highly organized neuropil structures such as the brain? We use the nematode C. elegans to look at the development of circuits in vivo and with single cell resolution.

The human brain consists of 100 billion neurons and over 100 trillion synapses. The ability of a neuron to find its correct target in this complex environment is critical for the formation of the circuits that underlie human behavior. What are the molecular and cellular “organizing principles” that help create such a complex, yet precisely wired structure?

Figure 1 (A) Cytoplasmic fluorophores specifically in interneuron AIY (red) and interneuron RIA (green). (B) Presynaptic vesicles in AIY (red) and postsynaptic glutamate receptors in RIA (green). Note how AIY innervates RIA specifically in a region termed “Zone 2” (dashed boxes). (C-F) Presynaptic vesicles in AIY in wild-type (C,E) or unc-40 mutants (D, F).  Note the significant reduction of presynaptic sites in Zone 2 in unc-40 mutants.

We have established a system in the C. elegans nerve ring (the nematode brain) to study this question.  In C. elegans we can visualize synapse development in vivo with single cell resolution, and use genetic and cell biological tools to dissect the molecular and cellular components required for the development of the nematode brain. Using this system we discovered that glial cells are required for the assembly of behavioral circuits in the brain. To our knowledge this is the first evidence that glial cells can specify precise neural connectivity in vivo.  We also discovered a novel function for the Netrin receptor UNC-40/DCC in directing synaptic targeting. 

These findings prompt the following questions:  How does the Netrin receptor direct synapse formation?  How do glial cells orchestrate circuit assembly in the brain?  What other molecular signals govern synaptic targeting in the nematode brain?  Our lab couples genetic, molecular and biochemical techniques to answer these questions and indentify the organizing principles that direct precise circuit connectivity in the nematode brain.

Publications

Colón-Ramos D.A., Shen K. (2008) Cellular conductors: glial cells as guideposts during neural circuit development. PLoS Biol. 6:e112.  

Colón-Ramos, D.A., Margeta, M., Shen, K., 2007, Glia promote local synaptogenesis through UNC-6/Netrin signaling in C. elegans.  Science, Oct 5; 318 (5847): 103-6  

Colón-Ramos D.A.*, Shenvi C.L.*, Weitzel, D.H., Gan E.C.,  Matts R., Cate J. and Kornbluth S., 2006, Direct ribosomal binding by a cellular inhibitor of translation. Nat. Struct. Mol. Biol.  Feb; 13 (2): 103-11  

Olson, M.R., Holley C. L., Gan E.C., Colón-Ramos D.A., Kaplan B., Kornbluth S., 2003, A link between mitochondrial localization and Reaper-mediated IAP destruction.  J. Biol. Chem. Nov; 278 (45):44758-68  

Colón-Ramos D.A., Irusta P., Gan E.C., Olson M.R., Song J., Morimoto R.I., Elliott R.M., Lombard M., Hollingsworth R., Hardwick J.M., Smith G.K., Kornbluth S., 2003, Inhibition of translation and induction of apoptosis by Bunyaviral Non-structural proteins bearing sequence similarity to Reaper.  Mol. Biol. Cell Oct; 14 (10) 4162-72  

Colón-Ramos D.A., Salisbury J., Sanders M., Shenoy S., Singer R., García-Blanco M.A., 2003,  Asymmetric distribution of nuclear pore complexes and the cytoplasmic localization on b2-tubulin mRNA in Chlamydomonas reinhardtii.  Dev. Cell Jun; 4(6):941-52.  

Holley C.L.*, Olson M.R.*, Colón-Ramos D.A.*, Kornbluth S., 2002, Reaper eliminates IAP proteins through stimulated IAP degradation and generalized translational inhibition.  Nat. Cell Biol. Jun; 4(6):439-44