Huffington Center On Aging - About HCOA

Adam Antebi, Ph.D.

Assistant Professor, Huffington Center on Aging Department of Molecular and Cellular Biology Baylor College of Medicine One Baylor Plaza, Room M-320 Houston, Texas 77030 phone: 713-798-6661; fax: 713-798-4161
aantebi@bcm.tmc.edu

Adam Antebi CV

Endocrine regulation of C. elegans metabolism, developmental age and aging
Dr. Adam Antebi, Huffington Center on Aging, Dept. of Molecular and Cellular Biology, Baylor College of Medicine

All animals develop through successive stages and have defined life spans determined by their genome and modulated by their environment. What determines a species life plan and life span? And how does the environment impact these processes? By studying the simple model organism C. elegans, we have discovered a nuclear hormone receptor (NHR) signaling pathway that retards maturation and aging in adverse environments. This pathway works in conjunction with Insulin/IGF signaling, revealing that evolutionary conserved endocrine networks dictate metazoan life histories. Our longterm aims are to elucidate the entire endocrine network, from signaling inputs, to hormone identity, production and transport, to transcriptional complexes and target genes and relate them to the regulation of metazoan developmental age and aging.

Our studies on C. elegans daf-12/NHR and its associated signaling pathway have pioneered the regulation of aging by NHR signaling. daf-12 is related to vertebrate vitamin D and liver-X receptors, and couples environmental cues to metabolism, diapause, developmental timing and longevity. Notably, in favorable environments, C. elegans undergoes reproductive development, while in adverse environments animals enter the dauer diapause, a developmentally arrested third larval (L3) stage that is stress resistant and long-lived (Figure 1).

Figure l. C. elegans modes of development. A) A reproductively growing fourth larval stage C. elegans hermaphrodite. B) A developmentally arrested third larval stage dauer larva.

	Our Team:
		Dr. Nicole Fielenbach Ph: 713-798-2117 nicolef@bcm.tmc.edu
		Dr. Veerle Rottiers Ph: 713-798-2117 rottiers@bcm.tmc.edu
		Axel Bethke Ph: 713-798-2117 abethke@bcm.tmc.edu

Molecular genetic studies suggest that insulin/IGF-I and TGF-beta signaling pathways integrate environmental cues, and produce downstream secondary signals that converge on DAF-12 to mediate this developmental choice (Figure 2). DAF-12´s molecular identity suggested these secondary signals could be a lipophilic hormone.

We provided an important link in these circuits when we found DAF-9, a cytochrome P450 (CYP450) related to steroidogenic hydroxylases, as an integrator of upstream inputs and a proximal regulator of DAF-12, suggesting that DAF-9(+) produces the DAF-12 ligand. More recently, we have identified a Rieske oxygenase as well as other hormone biosynthetic genes, outlining an entire hormone biosynthetic pathway (Figure 2). Finally, we showed that nuclear corepressor, DIN-1, a homolog of human SHARP, works as a ligand regulated coregulator, complexing with unliganded DAF-12 to specify slow life history traits.

Figure 2. Life history regulation by DAF-12/NHR. In favorable environments, Insulin/IGF and TGF-beta peptide signal converge on the nuclear receptor branch of the dauer pathways. Niemann-Pick C1 homologs NCR-1/2 deliver cholesterol to DAF-36/Rieske oxygenase and DAF-9/cytochrome P450, triggering synthesis of the dafachronic acids. In the presence of hormone, DAF-12/NHR assembles postulated coactivator complexes, and directs expression of genes involved in reproductive development, developmental advance, fat metabolism, and accelerated aging (fast life history traits). AGTGCA and CACACA define two distinct DAF-12 bindng sites. In unfavorable environments, hormonal pathways are suppressed. Unliganded DAF-12 together with DIN-1/corepressor specify programs of dauer diapause, delayed development, fat storage, and retarded aging (slow life history traits). Downregulated insulin/IGF-I signaling also has independent outputs for diapause and longevity (not shown).

If DAF-12 is indeed hormone regulated, what is the chemical identity of the DAF-12 ligand? Recently, in collaboration with Dr. David Mangelsdorf (UTSW) we have now identified two endogenous ligands to be bile acid-like 3-keto steroids containing a 26-S carboxy side chain (Figure 3). These ligands, called dafachronic acids, transcriptionally activate DAF-12 in the nM range, and like classical lipophilic ligands, dissociate the complex of nuclear receptor and corepressor. At the organismal level, they rescue larval defects of hormone deficient mutants, as well as mutants in upstream insulin/IGF-I and TGF-beta signaling pathways. These findings reveal that steroid control of reproduction is evolutionarily ancient. With ligand in hand, we are now investigating influences on life span, as well as target genes.

In addition to roles in diapause and aging, we also found that DAF-12 works in the heterochronic circuit, a regulatory hierarchy controlling developmental timing. C. elegans develops through four larval stages (L1-L4) to adult. Mutants in the heterochronic loci cause animals to repeat or delete stage specific cellular programs. Most of the identified components are evolutionarily conserved, including the first discovered microRNAs. DAF-12 specifies third and later larval stage programs; mutants repeat L2 programs at the L3 stage, including gonadal pathfinding and epidermal stem cell division patterns. Through further genetic screens we have identified other components of the heterochronic circuit, including a conserved F-box protein called DRE-1. How these various components work together to regulate developmental timing is an area of critical interest. Importantly, our finding that DAF-12 links dauer and heterochronic pathways, suggests that this receptor coordinates reproductive maturation to the sustainable environment. Conceivably, estrogen receptor may analogously regulate the pace of maturation in response to dietary, hormonal, and genetic inputs.

Figure 3. Chemical structure of DAF-12 ligands.

Selected Publications

1. Rottiers, V., Motola, D., Cummins. C.L, Gerisch,B., Nishiwaki, K., Mangelsdorf, D. and A. Antebi (2006) Hormonal control of C. elegans dauer formation and life span by a Rieske-like oxygenase, Dev Cell 10, 1-10.

2. Motola, D. Cummins,C.L., Rottiers, V., Sharma, K., Sunino, K. ,Xu, E., Auchus, R., Antebi, A. and D. Mangelsdorf (2006) Identification of hormonal ligands for DAF-12 that govern dauer formation and reproduction in C. elegans Cell, 124, 1209-23

3. A. Antebi (2005) The tick-tock of aging, Science 310, 1911-13.

4. A. Antebi (2005) “Nuclear hormone receptors in C. elegans” in Wormbook, an online resource for C. elegans . http://www.wormbook.org/ Ed. M. Chalfie, L. Girard.

5. Shostak, Y., Van Gilst, M.R., Antebi, A., and K. R. Yamamoto (2004) Identification of DAF-12 binding sites, response elements and target genes. Genes & Development 18, 2529-44.

6. Ludewig, A., Kober-Eisermann, C., Weitzel, C., Neubert, K., Bethke, A., Gerisch, G., Hutter, H. and A. Antebi (2004), A novel coregulator/nuclear receptor complex controls C. elegans larval development, fat metabolism and aging. Genes & Development 18, 2120-33.

7. Gerisch, B. and A. Antebi.(2004) Hormonal signals produced by DAF-9/cytochrome P450 regulate C. elegans dauer diapause in response to environmental cues. Development 131,1765-76.

8. Tatar, M., Bartke, A., and A. Antebi (2003), Endocrine Regulation of Aging by Insulin-like signals. Science 299, 1346-51.

9. Gerisch, B. Weitzel, C., Kober-Eisermann, C., Rottiers, V. and A. Antebi (2001) A hormonal signaling pathway influencing C. elegans metabolism, reproductive development and life span, Dev. Cell 1, 841-851.

10. Antebi, A., Yeh, W.H., Tait, D., Hedgecock, E.M. and D. Riddle1 (2000) daf-12 encodes a nuclear receptor that regulates the dauer diapause and developmental age in C. elegans. Genes & Dev 14, 1512-27.

11. Antebi, A., Culotti, J.G., and E.M. Hedgecock (1998) daf-12 regulates developmental age and the dauer alternative in C. elegans. Development 125, 1191-1205.