Associate Professor, Huffington Center on Aging; Departments of Molecular & Cellular Biology and Molecular and Human Genetics; Programs in Cell & Molecular Biology and Developmental Biology

B.A., Swarthmore College, Swarthmore, PA
Ph.D., Massachusetts Institute of Technology, Cambridge, MA
Postdoc, Johns Hopkins University, Baltimore, MD

RESEARCH INTERESTS:

Endocrine regulation of C. elegans metabolism, developmental age and aging: All animals develop through successive life stages and have life spans that are determined by their genome and modulated by the environment. By studying the simple nematode C. elegans we seek to uncover phyletically conserved pathways that determine a species life plan and life span. My laboratory has focused on a nuclear hormone receptor (NHR) signaling pathway that couples environmental cues, such as nutrient availability, to organismal alternatives of developmental arrest and slow aging versus rapid reproductive growth and fast aging.

daf-12 encodes a NHR transcription factor receptor most closely related to vertebrate vitamin D and liver-X receptors. It lies at the convergence of pathways regulating metabolism, dauer diapause, developmental timing, and life span. By applying conventional molecular genetic techniques as well as high throughput RNAi screens, we have identified many components of NHR signaling --from endocrine cells to molecules involved in lipophilic hormone biosynthesis and metabolism, as well as transcriptional coregulators and target genes. Our studies reveal that DAF-12 works as part of a hormone regulated switch that determines the animals development and life span. In particular, hormone deficient mutants constitutively enter the dauer diapause, a long lived larval stage, but recover to adults that are long lived as well. Longevity largely depends on DAF-12(+), revealing that the unliganded receptor can specify states of somatic endurance and extended survival. Recently, in collaboration with Dr. David Mangelsdorf (UTSW), we have identified two endogenous DAF-12 ligands to be bile acid-like 3-keto steroids. Ligand supplementation restores normal life span and stress resistance to hormone deficient mutants, providing some of the first evidence that such molecules regulate animal longevity. We are now exploring the molecular mechanisms by which ligand, receptor complexes, and target genes determine organismal physiology.

We have 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 heterochronic loci, including a conserved F-box protein called DRE-1. How these various components cooperate 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:

1. Fielenbach N, Guardavaccaro D, Neubert K, Chan T, Li D, Feng Q, Hutter H, Pagano M, Antebi A (2007). DRE-1, an evolutionarily conserved F-box protein that regulates C. elegans developmental age. Dev. Cell 12: 443-455.

2. Gerisch B, Rottiers V, Li D, Motola D, Cummins, CL, Lehrach H, Mangelsdorf D, Antebi A (2007). A bile acid-like steroid modulates C. elegans life span through nuclear receptor signaling. PNAS 104: 5014-5019.

3. Rottiers V, Motola D, Cummins CL, Gerisch B, Nishiwaki K, Mangelsdorf D, Antebi A (2006). Hormonal control of C. elegans dauer formation and life span by a Rieske-like oxygenase. Dev. Cell 10: 473-482.

4. Motola D, Cummins CL, Rottiers V, Sharma K, Sunino K, Xu E, Auchus R, Antebi A, Mangelsdorf D (2006). Identification of hormonal ligands for DAF-12 that govern dauer formation and reproduction in C. elegans. Cell 124: 1209-1223.

5. Shostak Y, Van Gilst MR, Antebi A, Yamamoto KR (2004). Identification of DAF-12 binding sites, response elements and target genes. Genes Dev. 18: 2529-2544.

6. Ludewig A, Kober-Eisermann C, Weitzel C, Neubert K, Bethke A, Gerisch G, Hutter H, Antebi A (2004). A novel coregulator/nuclear receptor complex controls C. elegans larval development, fat metabolism and aging. Genes Dev. 18: 2120-2133.

7. 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.

8. Tatar M, Bartke A, Antebi A (2003). Endocrine Regulation of Aging by Insulin-like signals. Science 299: 1346-1351.

9. 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. Dev. Cell 1: 841-851.

For more publications, see listing on Pub Med.

CONTACT INFORMATION:

Adam Antebi, Ph.D.
Huffington Center on Aging
Baylor College of Medicine
One Baylor Plaza, Rm M320, N803.02
Houston, Texas 77030, U.S.A.
Mail Stop: BCM230

Phone:713-798-6661 (office) 713-798-2117 (lab)
Fax: 713-798-4161
E-mail:

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