WIGHTMAN LAB PAGE

UNDERGRADUATE RESEARCH ON THE MOLECULAR GENETICS OF ANIMAL DEVELOPMENT

This work is supported by a grant from the National Science Foundation.

Laboratory of Bruce Wightman, Biology Department

New Science Building 221

Our laboratory is studying the mechanisms of animal development, using the nematode Caenorhabditis elegans as a model system. We perform experiments that include Mendelian genetic, molecular genetic, genomic, and biochemical approaches. Research students in our lab learn valuable technologies, help design experiments, interpret data, publish papers and attend scientific conferences.

CURRENT RESEARCH PROJECTS
The nuclear hormone receptors are a class of evolutionarily-conserved proteins that regulate transcription of other genes in all known animals, from coral to humans. In a variety of species, nuclear hormone receptors play critical roles in physiology and development. For example, the androgen receptors mediate male sex development, estrogen receptors function in female physiology, and ecdysone receptors control insect morphogenesis. Many, but not all, nuclear receptors are activated in response to small lipophilic hormones, such as estrogen. The small soil-dwelling roundworm C. elegans, like other nematodes, has seen an explosion in the number and variety of nuclear receptors. While humans have only 48 nuclear receptors, C. elegans has over 270. Our lab is focused on the NR2E class of nuclear receptors. In vertebrates, two genes of this class have been studied: PNR (NR2E3), which functions in the development of rod and cone photoreceptor neurons in human retina, and tailless, which functions in the development of adult neural stem cells and limbic system in mice. We are studying the C. elegans versions of these genes: fax-1 (PNR), nhr-67 (tailless), and nhr-111 (worm-specific).		Picture of nematode: Nuclear receptors regulate transcription of other genes by binding to promoter DNA sequences:
Molecular evolution of nuclear hormone receptor function in development
Each nuclear receptor has two important parts (domains) in the protein: the DNA-binding domain (DBD), which is the part that binds to DNA in the promoter of other genes, and the ligand-binding domain (LBD), which is the part that binds a hormone (if there is one) and mediates changes in the rate of transcription of genes that a regulated by the nuclear receptor. We are studying the DNA-binding properties of NR2E nuclear receptors in C. elegans. We have found that FAX-1 and NHR-67 bind distinct sequences and that the DNA-binding function of each protein is very similar to that of its fly and human equivalents. In contrast to the DBD, where amino acid sequence is very similar in worms, flies and humans, the sequence of the LBD is very different in worms as compared to other species. Furthermore, nematode LBD's tend to be quite different from each other. We are studying this problem by testing a series of "hybrid" genes that swap LBD's from various NR2E nuclear receptors and testing their function in vivo.
The function of nhr-67/tailless in uterus development and posterior pattern formation
In Drosophila, the tailless nuclear receptor functions in orchestrating the patterning of the embryonic termini-- heads and tails. We have genetic evidence that suggests that the nematode equivalent, nhr-67, functions in posterior pattern formation in the embryo, similar to Drosophila. We have also found that nhr-67 plays a key role in regulating the post-embryonic development of the C. elegans uterus. Our current work on this project is focused on placing the function of the nhr-67 gene in the Notch-based signaling pathway that directs formation of the ventral uterus. Understanding the Notch pathway has implications for understanding the molecular basis of Alzheimer Disease: a gene called sel-12 may function upstream of nhr-67. Mutations in a human equivalent of sel-12 lead to an inherited form of Alzheimer Disease. In mice and flies, tailless plays a key role in the development of the brain. Mice that are born with mutations in tailless have a severe loss of limbic system neurons and are hyper-aggressive. Other studies have shown that tailless functions in regulating the differentiation of neural stem cells. As in other animals, nhr-67 is expressed in neurons of C. elegans, and work in our lab is beginning to address whether tailless function in nervous system development is also conserved in nematodes. The function of unstudied related nuclear receptors The nhr-111 and nhr-239 gense are related to fax-1 and more loosely to the other NR2E genes. While C. elegans has an nhr-111 gene, the closely-related nematode C. briggsae does not. Our study of nhr-111 provides an opportunity to study the evolution of nuclear receptor function in species-specific development or behavior. In contrast, nhr-239 appears to be weakly-conserved in echinoderms and many invertebrates.

THE WIGHTMAN LABORATORY

PERSONNEL

Bruce Wightman, lab head
Sheila Clever, lab manager
Christopher Alvaro ('10)
Emily Brennan ('09)
Valerie Brown ('10)
Stephanie Eng ('10)
Jessica Nesmith ('09)
Brittany Sanford ('11)
John Schocken ('09)
Roxy Sholevar ('11)
Michael Twardzik ('09)

LAB ALUMNI

Alumni of the Wightman lab have gone on to pursue graduate and professional study at institutions such as Stanford University, Columbia University, Cornell University, University of Pennsylvania, and Yale University. They have won competitive awards such as the NSF Graduate Fellowship, British Marshall Scholarship, and Fulbright Scholarship.

Genna Albert '03
Peter Alff '02
Pujah Ahuja (Parkland HS)
Jennifer Baldwin '02
Sepi Bazel '03
Kelly Berg '03
Nick Bianco '01
David Brightbill '99
Nicole Carmean '98
Sara Carr
Angela Cenci '05
Andrea Cerrone '02
Genevieve Cheng ('06)
Melissa Cronin (Dickinson)
Christian Davidson '00
Rich DeMarco '98
Stephen DeMeo '04
Bryan Ebert '99
Michael Engels '06
Jessica Fiske-Baier (Emmaus HS)
Heidi Harrington '01
Rebecca Haviland '03
Jason Hauptman '01
Annie Jilozian '07
Chirag Kalola '99
Ryan Kennedy '04
Brook Kohrt '00
Bryn Lipovsky (Moravian)
Emily Lisco ('08)
Rebecca Lombel '03
Ryan Martin '02
Sonya Martinez-Hunsicker '06
Aaron Miller '00
Simone Moniz (Emmaus HS)
Elissa Murphy '00
Jason Much (F&M)
Ameet Nagpal '03
Jill Neiman '06
Son Nguyen '98
Rick Oravec '06
Suchi Pandey '99
Doug Prechtel (Virginia Tech)
Galina Radzievsky '00
Kristy Reinert '02
Corrine Rennig '06
Rebecca Royce (Virginia Tech)
Gwen Sarver '99
Michelle Seif '06
Dennis Slade '99
Eric Smith '02
Danielle Snowflack '03
Matthew Stein (Haverford)
Tilak Sundaresan '02
Jessica Tanis '02
Veronica Taylor ('09)
Eliana Verghese ('08)
Aaron Wagner '05
Katie Weber (U. Richmond)
Hillel Wiener
Kelly Klampert (Technician)

RECENT PUBLICATIONS AND PRESENTATIONS

DeMeo, S., Lombel, R., Snowflack, D., Smith, E., Reinert, K., Cronin, M., Clever, S., and B. Wightman, 2008, Specificity of DNA-binding by the FAX-1 and NHR-67 nuclear receptors of Caenorhabditis elegans is partially mediated via a subclass-specific P-box residue, BMC Molecular Biology, 9:2.

Wightman, B., N. Carmean, B. Ebert, K. Weber, and S. Clever, 2005, The C. elegans nuclear receptor gene fax-1 and homeobox gene unc-42 coordinate interneuron identity by regulating the expression of glutamate receptor subunits and other neuron-specific genes, Developmental Biology, 287: 74-85.

Much, J. W., D. J. Slade, K. Klampert, G. Garriga and B. Wightman, 2000, The fax-1 nuclear hormone receptor regulates axon pathfinding and neurotransmitter expression, Development 127: 703-712.

C. Alvaro, K. Weber, J. Fiske-Baier, S. Clever, B. Wightman, 2008, Function and phylogenetics of the NR2E nuclear receptors in C. elegans, presentation (CA) at the Society for Developmental Biology 67^th Annual Meeting, Philadelphia, PA, July 26-30.

J. Schocken, E. Verghese, E. Lisco, S. Eng, M. Twardzik, V. Brown, B. Sanford, S. Bywaters, E. McCain, B. Wightman, 2008, The C. elegans tailless ortholog nhr-67 functions in uterus and tail development, presentation (JS, EL, VB, BS, SB) at the Society for Developmental Biology 67^th Annual Meeting, Philadelphia, PA, July 26-30.

B.Wightman, E. Verghese, M. Twardzik, E. Lisco, S. Clever, 2008, The tailless ortholog nhr-67 functions in uterus, tail, and germ-line development, presentation (BW) at the Conference on Development and Evolution, U. Wisconsin, Madison, WI, June 11-15. *Second Place Award in Poster Competition*

E. Verghese, R. Royce, R. Oravec, S. Clever, B. Wightman, 2007, A conserved nuclear receptor, nhr-67, functions in uterus development and posterior pattern formation, presentation (EV) at the Undergraduate Research at the Capitol Symposium, October 2, Harrisburg, PA.

K. P. Weber and B. Wightman, 2007, Conservation of ligand binding domain function among NR2E nuclear receptors, presentation (KW) at the 16^th International C. elegans Conference, Los Angeles, CA, June 28.

E. Verghese, R. Royce, R. Oravec, S. Clever, B. Wightman, 2007, The nuclear receptor gene nhr-67 functions in uterus development and posterior pattern formation, presentation (EV) at the 16^th International C. elegans Conference, Los Angeles, CA, June 30.

K. Weber, G. Cheng and B. Wightman, 2006, Ligand binding domain function of C. elegans nuclear receptors, presentation (KW) at the 9^th Annual Undergraduate Research Symposium, U. Maryland, Baltimore Co., Baltimore, MD, Oct. 14. *Second Place Award in Poster Competition*

R. M. Royce and B. Wightman, 2006, The nhr-67 gene of Caenorhabditis elegans encodes a tailless ortholog that regulates uterus development, presentation (RMR) at the 9^th Annual Undergraduate Research Symposium, U. Maryland, Baltimore Co., Baltimore, MD, Oct. 14.

K. Weber, S. Clever, S. DeMeo, R. Lombel, D. Snowflack, M. Cronin, and B. Wightman, 2006, Domain functions of NR2E nuclear receptors, presentation (KW) at the Conference on Development and Evolution, U. Wisconsin, Madison, WI, June 22-25.

B. Wightman, J. Neiman, A. Cenci, and S. Clever, 2006, The nuclear receptor gene nhr-67 functions in uterine development, presentation (BW) at the Conference on Development and Evolution, U. Wisconsin, Madison, WI, June 22-25.

Neiman, J., Cenci, A., and B. Wightman, 2005, The C. elegans nuclear receptor gene nhr-67 functions in uterine development, presentation (JN) at the 8th Annual Undergraduate Research Symposium, U. Maryland, Baltimore Co., Baltimore, MD, Oct. 15.

Wightman, B., Weber, K., DeMeo, S. (’04), Lombel, R., Snowflack, D., Cronin, M., Cenci, A., Wagner, A., Seif, M., Clever, S., 2005, The NR2E nuclear receptors: fax-1 and nhr-67, presentation (BW) at the 15th International C. elegans Conference, Los Angeles, CA, June 25-29.

Wightman, B., and S. Clever, 2004, The nuclear receptor gene fax-1 and homeobox gene unc-42 coordinate interneuron identity by regulating the expression of glutamate receptor subunits and other neuron-specific genes, presentation (BW and SC) at the 2004 East Coast C. elegans Meeting, Yale University, New Haven, CT, June 11 – 13.

Kennedy, R., Reinert, K., Albert, G., Gissendanner, C., Sluder, A., and B.Wightman, 2004, nhr-67 and nhr-111, two NR2E nuclear receptors that may function in nervous system development, presentation (RK) at the 2004 East Coast C. elegans Meeting, Yale University, New Haven, CT, June 11 – 13.

DeMeo, S., Lombel, R., Snowflack, D., Wagner, A., Smith, E., Clever, S., and B. Wightman, 2004, Degenerate binding sites for the FAX-1 nuclear receptor predict potential downstream target genes, presentation (SD) at the 2004 East Coast C. elegans Meeting, Yale University, New Haven, CT, June 11 – 13.

Wightman, B., S. DeMeo, A. Wagner, R. Lombel, D. Snowflack, E. Smith, A. Nagpal, and K. Reinert, 2004, Regulation of interneuron-specific gene expression by the C. elegans fax-1 (NR2E5) nuclear receptor, presentation (BW) at the 2004 Keystone Symposium (International Conference), Nuclear Receptors: Orphan Brothers, Keystone, CO, February 28-March 4.

Lombel, R., R. Haviland, E. Smith, and B. Wightman, 2003, Nuclear hormone receptor fax-1 functions in determination of neuron identity in C. elegans, presentation (RL and RH) at the AAAS Annual Meeting, Denver, CO, February 13-18.

Albert, G., S. Mathieson, and B. Wightman, 2002, Molecular analysis of nhr-67 and nhr-111: Two C. elegans nuclear hormone receptors, presentation (GA) at the 2002 Kimmel Cancer Center Undergraduate Poster Symposium, Philadelphia, PA, October 21.

Tanis, J, P. Alff, J. Doto, D. Hall, E. McCain, and B. Wightman, 2002, Structural differences in the golgi apparatuses of wild-type and unc-20 mutant adults, presentation (JT) at the 2002 East Coast C. elegans Meetings, Durham, NH, June 14-16.

Smith, E.L., R. Haviland, R. Lombel, S. Mathieson, and B. Wightman, 2002, Coordinate regulation of glutamate receptors and ncs-1 in interneurons by fax-1 and unc-42, presentation (ES, RH and RL) at the 2002 East Coast C. elegans Meetings, Durham, NH, June 14-16.

Reinert, K. and B. Wightman, 2002, Expression of nhr-111, an apparent C. elegans-specific nuclear hormone receptor, presentation (KR) at the 2002 East Coast C. elegans Meetings, Durham, NH, June 14-16.

Sundaresan, T., S. Mathieson, K. Reinert, E. Murphy, J. Tanis, N. Bianco, R. Martin, Y. Vidgop, B. Wightman, 2001, The FAX-1 nuclear hormone receptor functions downstream of other transcriptional regulators to specify neuron identity, presentation (TS and SM) at the 13th International C. elegans Meeting, Los Angeles, June 22-26.

Tanis, J., P. Alff, B. Kohrt, J. Doto, B. Wightman, 2001, unc-20 maps to a region that includes two predicted golgi complex proteins, presentation (JT and PA) at the 13th International C. elegans Meeting, Los Angeles, June 22-26.

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