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Endocrine regulation of C. elegans metabolism, developmental age and aging
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 evolutionarily 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. Molecular genetic studies suggest that insulin/IGF-I and TGF-β
signaling pathways integrate environmental cues, and produce downstream secondary signals that converge on DAF-12 to
mediate this developmental choice. 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. 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.
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. 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-β
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.
Selected Publications
Antebi A, Yeh WH, Tait D, Hedgecock EM, Riddle DL (2000) daf-12 encodes a nuclear receptor that
regulates the dauer diapause and developmental age in C. elegans. Genes and Development 14:1512-1527.
Gerisch B, Weitzel C, Kober-Eisermann C, Rottiers V, Antebi A (2001) A hormonal signaling pathway
influencing C. elegans metabolism, reproductive development, and life span. Developmental Cell
1:841-851.
Tatar M, Bartke A, Antebi A (2003) The endocrine regulation of aging by insulin-like signals.
Science 299:1346-1351.
Gerisch B, Antebi A (2004) Hormonal signals produced by DAF-9/cytochrome P450 regulate C. elegans
dauer diapause in response to environmental cues. Development 131:1765-1776.
Ludewig AH, Kober-Eisermann C, Weitzel C, Bethke A, Neubert K, Gerisch B, Hutter H, Antebi A (2004) A
novel nuclear receptor/coregulator complex controls C. elegans lipid metabolism, larval development, and aging.
Genes and Development 18:2120-2133.
Shostak Y, Van Gilst MR, Antebi A, Yamamoto KR (2004) Identification of C. elegans DAF-12-binding
sites, response elements, and target genes. Genes and Development 18:2529-2544.
Antebi A (2005) “Nuclear hormone receptors in C. elegans” in
Wormbook, an online resource for C. elegans. Ed. M.
Chalfie, L. Girard.
Antebi A (2005) The tick-tock of aging? Science 310:1911-1913.
Motola DL, Cummins CL, Rottiers V, Sharma KK, Li T, Li Y, Suino-Powell K, Xu HE, Auchus RJ, Antebi A, Mangelsdorf DJ (2006)
Identification of ligands for DAF-12 that govern dauer formation and reproduction in C. elegans. Cell 124:1209-1223.
Rottiers V, Motola DL, Gerisch B, Cummins CL, Nishiwaki K, Mangelsdorf DJ, Antebi A (2006) Hormonal control of C. elegans
dauer formation and life span by a Rieske-like oxygenase. Developmental Cell 10:473-482.
Contact Information
- Adam Antebi, Ph.D.
- Huffington Center on Aging
- Baylor College of Medicine
- One Baylor Plaza, N803.02
- Houston, Texas 77030, U.S.A.
- Tel: (713) 798-6661
- Fax: (713) 798-4161
- E-mail: aantebi@bcm.tmc.edu
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