Steroid Regulation of C. elegans Diapause, Developmental Timing, and Longevity

doi:10.1016/B978-0-12-396968-2.00007-5

Current Topics in Developmental Biology

Volume 105, 2013, Pages 181-212

https://doi.org/10.1016/B978-0-12-396968-2.00007-5 Get rights and content

Abstract

Hormones play a critical role in driving major stage transitions and developmental timing events in many species. In the nematode C. elegans the steroid hormone receptor, DAF-12, works at the confluence of pathways regulating developmental timing, stage specification, and longevity. DAF-12 couples environmental and physiologic signals to life history regulation, and it is embedded in a rich architecture governing diverse processes. Here, we highlight the molecular insights, extraordinary circuitry, and signaling pathways governing life stage transitions in the worm and how they have yielded fundamental insights into steroid regulation of biological time.

Introduction

Hormones play a key role in coordinating metabolism, reproduction, and homeostasis in all metazoans. Some of the earliest seminal discoveries on endocrine mechanisms revealed how small molecular metabolites govern major maturational transitions. These include estrogens/androgens in mammalian puberty, thyroid hormone in amphibian metamorphosis, and ecdysteroids during insect molting and metamorphosis (Mangelsdorf and Evans, 1995, Mangelsdorf et al., 1995). These small molecules bind to cognate nuclear hormone receptor transcription factors androgen, estrogen, thyroid hormone, and the ecdysone receptors, respectively and thereby work as switches to direct broad changes in gene expression that drive developmental transitions.

Nuclear receptors have a conserved architecture, which underlie their signaling capacity. The N-terminus contains paired zinc fingers that constitute the DNA-binding domain, while the C-terminus harbors the ligand-binding domain (LBD), which also serves to recruit coactivator and corepressor complexes. Typically, nuclear receptors activate transcription in the presence of ligand, and in some cases they can repress the same genes in the absence of ligand (Mangelsdorf and Evans, 1995, Mangelsdorf et al., 1995).

The molecular mechanism of steroid receptor signal transduction is conserved in C. elegans and exemplified in the nuclear receptor DAF-12. DAF-12 is most homologous to vertebrate farnesoid-X (FXR), liver-X, and vitamin-D receptors, and it binds to bile acid-like steroids called the dafachronic acids (DAs), which regulate its transcriptional activity (Antebi et al., 2000, Motola et al., 2006). Because of the worm’s relative simplicity and powerful genetics, dissection of steroid signaling has illuminated important and novel facets of metazoan life history regulation. DAF-12 controls broad aspects of C. elegans maturation, including regulation of developmental arrest at the long-lived dauer stage, progression from second-to third-larval stage programs in developmental timing circuits, and organismal longevity. DAF-12’s essential role in these processes is to couple environmental and physiologic information to the precise timing of reproductive development. In each context, it is embedded in a remarkably rich circuitry, whose elucidation has yielded major insights into endocrine regulation of metazoan reproductive commitments, developmental timing, and longevity. Here, the author reviews the role of steroid receptor DAF-12 in the framework of these circuits.

Section snippets

C. elegans life history

All animals have the ability to sense environmental quality and nutrient availability, and adjust rates of maturation accordingly. In favorable environments, C. elegans develops rapidly from embryo through four larval stages (L1–L4) marked by molts to adulthood in about 3.5 days, termed reproductive development. They produce progeny for a week, and then typically live another two weeks. In unfavorable environments marked by food scarcity, elevated temperatures, and overcrowding indicated by

Heterochronic genes

In the course of animal development, cells throughout the body acquire both temporal and positional identities. As C. elegans develops from embryo through four larval stages L1–L4 and on to adult, each stage elaborates a characteristic array of cellular programs of division, differentiation, morphogenesis/migration, and death. In particular, certain tissues are explicitly temporally patterned, including division patterns of epidermal seam cells and intestinal cells, or morphogenesis of the

Hormonal Control of Longevity

Pioneering studies in the worm have illuminated conserved signaling pathways that regulate longevity. Several pathways have emerged that regulate longevity across taxa including reduced IIS, mitochondrial function, dietary-restriction-mediated longevity, and signaling from the gonad (Kenyon, 2010). Below, we highlight recent discoveries linking heterochronic functions and hormonal signaling to the gonadal longevity pathway.

Perspectives

Pioneering studies in C. elegans reveal that environmental cues are integrated by major growth factor pathways, including IIS and TGF-β signaling, which converge on steroidal receptor DAF-12. Depending on DA availability DAF-12 either triggers reproductive maturation by activating let-7 family microRNAs, catalyzing stage transitions through the body, or quiescence by shutting down the heterochronic and molting timers. Some of the same components that regulate developmental timing and metabolism

Acknowledgments

The author would like to thank members of the Antebi lab for reading the manuscript, and Dr. Birgit Gerisch for help with the figures. The author apologizes to those colleagues whom he could not cite due to length restrictions.

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Chapter Seven - Steroid Regulation of C. elegans Diapause, Developmental Timing, and Longevity

Abstract

Introduction

Section snippets

C. elegans life history

Heterochronic genes

Hormonal Control of Longevity

Perspectives

Acknowledgments

Developmental Cell

Cell

Developmental Biology

Molecular Cell

Developmental Cell

Cell

Developmental Cell

Developmental Biology

Developmental Biology

Developmental Biology

Cell Metabolism

Cell

Developmental Biology

Cell

Cell Metabolism

Developmental Biology

In J Steroid Biochem Mol Biol

Cell

Current Biology

Cell

Cell

Cell

Current Biology

Cell

Cell

Cell Metabolism

Developmental Biology

Current Biology

Developmental Cell

Developmental Biology

Molecular Cell

Identification of heterochronic mutants in Caenorhabditis elegans: Temporal misexpression of a collagen::green fluorescent protein fusion gene

Genetics

Alterations in xenobiotic metabolism in the long-lived Little mice. Aging cell

Heterochronic mutants of the nematode C. elegans

Science

Starvation protects germline stem cells and extends reproductive longevity in C. elegans

Science

daf-12 regulates developmental age and the dauer alternative in Caenorhabditis elegans

Development

daf-12 encodes a nuclear receptor that regulates the dauer diapause and developmental age in C. elegans

Genes & Development

Regulation of life-span by germ-line stem cells in Caenorhabditis elegans

Science

The conserved nuclear receptor Ftz-F1 is required for embryogenesis, moulting and reproduction in Caenorhabditis elegans

Genes to Cells

Heat shock factor-1 intertwines insulin/IGF-1, TGF-beta and cGMP signaling to control development and aging

BMC Developmental Biology

Co-option of the hormone-signalling module dafachronic acid-DAF-12 in nematode evolution

Nature

Nuclear hormone receptor regulation of microRNAs controls developmental progression

Science

Estradiol-regulated microRNAs control estradiol response in breast cancer cells

Nucleic Acids Research

A developmental timing microRNA and its target regulate life span in C. elegans

Science

Small-molecule pheromones that control dauer development in Caenorhabditis elegans

Nature Chemical Biology

Trim71 cooperates with microRNAs to repress Cdkn1a expression and promote embryonic stem cell proliferation

Nature Communications

Hormonal activation of let-7-C microRNAs via EcR is required for adult Drosophila melanogaster morphology and function

Development

DAF-5 is a Ski oncoprotein homolog that functions in a neuronal TGF beta pathway to regulate C. elegans dauer development

Development

Post-embryonic expression of C. elegans microRNAs belonging to the lin-4 and let-7 families in the hypodermis and the reproductive system

Developmental Dynamics

The daf-4 gene encodes a bone morphogenetic protein receptor controlling C. elegans dauer larva development

Nature