Muhlenberg College

UNDERGRADUATE RESEARCH ON THE MOLECULAR GENETICS OF ANIMAL DEVELOPMENT

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Research at Muhlenberg
National Science Foundation

This work was 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), nhr-111 (worm-specific), and nhr-239 (found in most animals except vertebrates). 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. 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, our lab showed that the LBD is not required for some functions, suggesting that C. elegans nuclear receptors may sometimes be ligand-independent.

 

Picture of nematode:

Nuclear receptors regulate transcription of other genes by binding to promoter DNA sequences:

 

Function of fax-1 in cell migration and neuronal control of developmental progression


The FAX-1 nuclear receptor of C. elegans functions in neuron identity and is orthologous to vertebrate PNR nuclear receptor (NR2E3). In humans, mutations in PNR lead to defects in photoreceptor development and subsequent retinal degeneration.  The C. elegans hermaphrodite distal tip cells (DTCs) are responsible for leading the extension and formation of the hermaphrodite gonad. FAX-1 protein is expressed in both DTCs during their migratory period.  Mutations in fax-1 cause defects in the migration of the DTCs, most frequently in successful completion of the dorsal turn. Mutations in vab-3/Pax6, which cause continued migration of the DTCs into adulthood, also cause continued expression of fax-1::gfp in the DTCs into adulthood, indicating that fax-1 expression is a property of a migratory DTC.  In males, FAX-1 is also expressed in both the migratory linker cell (LC), where it is required for migration, and stationary DTCs.  This suggests that fax-1 may also have a role in gametogenesis, the main function of the stationary male DTCs.  fax-1 hermaphrodites display reduced brood size, suggestive of gametogenesis defects.

fax-1 mutants also exhibit a slow growth phenotype, which I determined to be a result of a defect in execution of the L1 transition.  Newly hatched C. elegans larvae (L1s) make a developmental decision to either initiate growth or arrest development, based on whether or not food is available.  Arrested L1 animals then resume growth once in the presence of food. fax-1 mutants undergo a temporary L1 arrest when hatching in the presence of food, likely a consequence of fax-1 function in the nervous system. We are currently exploring which interneurons are responsible for this function.

Emily at microscope
 

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.

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. Data suggest that nhr-111 may function as an important regulator of genes that function in metabolism. In contrast, nhr-239 appears to be weakly-conserved in non-vertebrate animals. Mutations in nhr-111 and nhr-239 do not cause dramatic, obvious phenotypes (death, sterility, major developmental defects). A deletion that removes the first exon and promoter of nhr-239 causes an interesting behavioral defect: worms avoid large concentrations of bacteria, suggesting they may be responding adversely to low oxygen environments.

Dominic

THE WIGHTMAN LABORATORY

 

PERSONNEL

 

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
Christopher Alvaro ('10)
Pujah Ahuja (Parkland HS)
G. Michael Baer ('12)
Jennifer Baldwin '02
Sepi Bazel '03
Kelly Berg '03
Nick Bianco '01
Alex Breiding ('11)
Emily Brennan ('09)
David Brightbill '99
Valerie Brown ('10)
Ramzy Burns ('14)
Nicole Carmean '98
Sara Carr
Angela Cenci '05
Andrea Cerrone '02
Genevieve Cheng ('06)
Jessica Chu ('12)
Melissa Cronin (Dickinson)
Christian Davidson '00
Rich DeMarco '98
Stephen DeMeo '04
Rachel Dordal ('14)
Bryan Ebert '99
Stephanie Eng ('10)
Michael Engels '06
Catherine Ezzio ('13)
Jessica Fiske-Baier (Emmaus HS)
Evan Fletcher ('13)
Amanda Gavin ('12)
Jennifer Hall ('12)
Rachel Halpern ('14)
Heidi Harrington '01
Rebecca Haviland '03
Jason Hauptman '01
Annie Jilozian '07
Chirag Kalola '99
Sabrina Kamran ('13)
Ryan Kennedy '04
Brook Kohrt '00
Dominic Lapadula (’14)
Bryn Lipovsky (Moravian)
Emily Lisco ('08)
Rebecca Lombel '03
Ryan Martin '02
Sonya Martinez-Hunsicker '06
George McClung ('12)
Aaron Miller '00
Simone Moniz (Emmaus HS)
Corrie Morris ('16)
Elissa Murphy '00
Jason Much (F&M)
Ameet Nagpal '03
Jill Neiman '06
Jessica Nesmith ('09)
Son Nguyen '98
Rick Oravec '06
Suchi Pandey '99
Anvi Patel ('12)
Benjamin Perlman ('13)
Lauren Pioppo ('12)
Doug Prechtel (Virginia Tech)
Galina Radzievsky '00
Kristy Reinert '02
Corrine Rennig '06
Rebecca Royce (Virginia Tech)
Brittany Sanford ('11)
Gwen Sarver '99
Peter Schartel ('15)
John Schocken ('09)
Michelle Seif '06
Zachary Shuler ('15)
Dan Sphilsky ('10)
Roxy Sholevar ('11)
Dennis Slade '99
Eric Smith '02
Danielle Snowflack '03
Matthew Stein (Haverford)
Rachel Summer ('12)
Tilak Sundaresan '02
Jessica Tanis '02
Tara Tappen ('11)
Veronica Taylor ('09)
Michael Twardzik ('09)
Eliana Verghese ('08)
Jessica Verzella ('12)
Aaron Wagner '05
Katie Weber (U. Richmond)
Hillel Wiener
Tiffany Zehner ('10)

Kelly Klampert (Technician)

Sheila Clever, lab manager

Lab Summer 2012

ZachRachel Pearly

Eliana

summer 2007

RECENT PUBLICATIONS AND PRESENTATIONS

D. Lapadula, P. Ezzio, L. Pioppo, M. Kho, P. Schartel, Z. Shuler, C. Greco, M. Kramer, S. Clever, B. Wightman, 2014, a promoter element in the C. elegans tailless gene links sex-specific regulation with uterine organogenesis, presentation (DL) at the 2014 Mid-Atlantic Society for Developmental Biology Meeting, Baltimore MD, May 30-31.

E. Bayer, B. Wightman, 2014, the conserved nuclear receptor fax-1 functions in C. elegans cell migration and neuronal regulation of lifecycle, presentation (EB) at the 2014 Mid-Atlantic Society for Developmental Biology Meeting, Baltimore MD, May 30-31.

E. Bayer, B. Wightman, 2013, Function of the conserved nuclear receptor fax-1 in C. elegans cell migration and sleep regulation presentation (EB) at the 16th Undergraduate Research Symposium, U. Maryland, Baltimore Co., Baltimore, MD, Oct. 26. Regional Conference. *First Place Award in Poster Competition*

D. Lapadula, P. Ezzio, S. Clever and B. Wightman, 2013, A promoter element in the C. elegans tailless gene links sex-specific regulation with uterine organogenesis, presentation (DL) at the 16th Undergraduate Research Symposium, U. Maryland, Baltimore Co., Baltimore, MD, Oct. 26. Regional Conference. *First Place Award in Poster Competition*

E. Bayer and B. Wightman, 2013,  fax-1 and prominin function in migration and morphogenesis, presentation (BW) at the 19th International C. elegans Meeting, Los Angeles, CA, June 26-30. International Conference.

E. Bayer and B. Wightman, 2012, Function of the conserved nuclear receptor nhr-239 in Caenorhabditis elegans, presentation (EB) at the 15th Undergraduate Research Symposium, U. Maryland, Baltimore Co., Baltimore, MD, Oct. 20. *First Place Award in Poster Competition* Regional Conference.

E. Bayer and B. Wightman, 2012, Function of the conserved nuclear receptor nhr-239 in Caenorhabditis elegans, presentation (EB) at the 15th Undergraduate Research Symposium, U. Maryland, Baltimore Co., Baltimore, MD, Oct. 20. *First Place Award in Poster Competition*

S. Kamran, C. Ingersoll, and B. Wightman, 2012, Function of nuclear receptor nhr-111 in lipid metabolism in C. elegans, presentation (SK) at the 15th Undergraduate Research Symposium, U. Maryland, Baltimore Co., Baltimore, MD, Oct. 20.

C. Ezzio and B. Wightman, 2012, Identifying upstream regulators of nhr-67 in C. elegans uterine development, presentation (CE) at the 15th Undergraduate Research Symposium, U. Maryland, Baltimore Co., Baltimore, MD, Oct. 20.

E.  Bayer, G. M. Baer , C. Alvaro, K. Weber, R. Burns, M. Lilly, A. Patel, B. Perlman, S. Clever, and B. Wightman, 2012, Function and evolution of the diverged NR2E nuclear receptors nhr-111 and nhr-239, presentation (EB) at the Cell and Developmental Biology Meeting, Madison, WI, June 7-10.

G. McClung, L. Pioppo, J. Hall, R. Dordal, C. Ezzio, E. Fletcher, A. Gavin, S. Clever, and B. Wightman, 2012, Regulation and function of nhr-67/tailless in uterus development, presentation (GM) at the Cell and Developmental Biology Meeting, Madison, WI, June 7-10.

Weber, K. P., Alvaro, C. G., Baer, G. M., Reinert, K., Cheng, G., Clever S., Wightman, B., 2012, Analysis of C. elegans NR2E nuclear receptors defines three conserved clades and ligand-independent functions, BMC Evolutionary Biology, 12:81.

Verghese, E., Schocken, J., Jacob, S., Wimer, A. M., Royce, R., Nesmith, J.E., Baer, G.M., Clever, S., McCain, E., Lakowski, B., and B. Wightman, 2011, The tailless ortholog nhr-67 functions in the development of the C. elegans ventral uterus, Developmental Biology, 356: 516-28.

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.

G. M. Baer, C. Alvaro, B. Perlman, and B. Wightman, 2011, A Possible Role for nhr-239 in Sensory Response, presentation (GMB) at the 18th International C. elegans Meeting, Los Angeles, CA, June 22-26.

T. Tappen, L. Pioppo, B. Sanford, J. Hall, G. McClung, R. Summer, A. Breiding, S. Clever, and B. Wightman, 2011, nhr-67/tailless Functions in the AC-VU Decision, AC Differentiation, and Expression of lin-12 in the pre-VU Cells, presentation (TT and LP) at the 18th International C. elegans Meeting, Los Angeles, CA, June 22-26.

B. Wightman, C. Alvaro, T. Zehner, K. Weber, S. Clever, 2010, Function and phylogenetics of the NR2E nuclear receptors, presentation (BW) at the Evolutionary Biology of Caenorhabditis and Other Nematodes Conference, Hinxton, Cambridge, UK, June 5-8.

C. Alvaro, T. Zehner, K. Weber, B. Wightman, 2009, Function and phylogenetics of the NR2E nuclear receptors, presentation (CA and TZ) at the 17th International C. elegans Meeting, Los Angeles, CA, June 24-28.

B. Sanford, E. Verghese, J. Schocken , J. Nesmith, S. Clever, and B. Wightman, 2009, The tailless ortholog nhr-67 functions in ventral uterus development, presentation (BS and BW) at the 17th International C. elegans Meeting, Los Angeles, CA, June 24-28.

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 67th 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 67th 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 16th 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 16th 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 9th 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 9th 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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