An official website of the United States government
Abstract In almost all animals, physiologically low oxygen (hypoxia) during development slows growth and reduces adult body size. The developmental mechanisms that determine growth under hypoxic conditions are, however, poorly understood. Here we show that the growth and body size response to moderate hypoxia (10% O 2 ) in Drosophila melanogaster is systemically regulated via the steroid hormone ecdysone. Hypoxia increases level of circulating ecdysone and inhibition of ecdysone synthesis ameliorates the negative effect of low oxygen on growth. We also show that the effect of ecdysone on growth under hypoxia is through suppression of the insulin/IGF-signaling pathway, via increased expression of the insulin-binding protein Imp-L2 . These data indicate that growth suppression in hypoxic Drosophila larvae is accomplished by a systemic endocrine mechanism that overlaps with the mechanism that slows growth at low nutrition. This suggests the existence of growth-regulatory mechanisms that respond to general environmental perturbation rather than individual environmental factors.
more »
« less
Dauer fate in a Caenorhabditis elegans Boolean network model
Cellular fates are determined by genes interacting across large, complex biological networks. A critical question is how to identify causal relationships spanning distinct signaling pathways and underlying organismal phenotypes. Here, we address this question by constructing a Boolean model of a well-studied developmental network and analyzing information flows through the system. Depending on environmental signals Caenorhabditis elegans develop normally to sexual maturity or enter a reproductively delayed, developmentally quiescent ‘dauer’ state, progressing to maturity when the environment changes. The developmental network that starts with environmental signal and ends in the dauer/no dauer fate involves genes across 4 signaling pathways including cyclic GMP, Insulin/IGF-1, TGF- β and steroid hormone synthesis. We identified three stable motifs leading to normal development, each composed of genes interacting across the Insulin/IGF-1, TGF- β and steroid hormone synthesis pathways. Three genes known to influence dauer fate, daf-2 , daf-7 and hsf-1 , acted as driver nodes in the system. Using causal logic analysis, we identified a five gene cyclic subgraph integrating the information flow from environmental signal to dauer fate. Perturbation analysis showed that a multifactorial insulin profile determined the stable motifs the system entered and interacted with daf-12 as the switchpoint driving the dauer/no dauer fate. Our results show that complex organismal systems can be distilled into abstract representations that permit full characterization of the causal relationships driving developmental fates. Analyzing organismal systems from this perspective of logic and function has important implications for studies examining the evolution and conservation of signaling pathways.
more »
« less
- PAR ID:
- 10434547
- Date Published:
- Journal Name:
- PeerJ
- Volume:
- 11
- ISSN:
- 2167-8359
- Page Range / eLocation ID:
- e14713
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
More Like this
-
-
Diapause is a state of developmental arrest adopted in response to or in anticipation of environmental conditions that are unfavorable for growth. In many cases, diapause is facultative, such that animals may undergo either a diapause or a non-diapause developmental trajectory, depending on environmental cues. Diapause is characterized by enhanced stress resistance, reduced metabolism, and increased longevity. The ability to postpone reproduction until suitable conditions are found is important to the survival of many animals, and both vertebrate and invertebrate species can undergo diapause. The decision to enter diapause occurs at the level of the whole animal, and thus hormonal signaling pathways are common regulators of the diapause decision. Unlike other types of developmental arrest, diapause is programmed, such that the diapause developmental trajectory includes a pre-diapause preparatory phase, diapause itself, recovery from diapause, and post-diapause development. Therefore, developmental pathways are profoundly affected by diapause. Here, I review two conserved hormonal pathways, insulin/IGF signaling (IIS) and nuclear hormone receptor signaling (NHR), and their role in regulating diapause across three animal phyla. Specifically, the species reviewed are Austrofundulus limnaeus and Nothobranchius furzeri annual killifishes, Caenorhabditis elegans nematodes, and insect species including Drosophila melanogaster , Culex pipiens , and Bombyx mori . In addition, the developmental changes that occur as a result of diapause are discussed, with a focus on how IIS and NHR pathways interact with core developmental pathways in C. elegans larvae that undergo diapause.more » « less
-
Murphy, Coleen T. (Ed.)Animals can adapt to dynamic environmental conditions by modulating their developmental programs. Understanding the genetic architecture and molecular mechanisms underlying developmental plasticity in response to changing environments is an important and emerging area of research. Here, we show a novel role of cAMP response element binding protein (CREB)-encoding crh-1 gene in developmental polyphenism of C . elegans . Under conditions that promote normal development in wild-type animals, crh-1 mutants inappropriately form transient pre-dauer (L2d) larvae and express the L2d marker gene. L2d formation in crh-1 mutants is specifically induced by the ascaroside pheromone ascr#5 (asc-ωC3; C3), and crh-1 functions autonomously in the ascr#5-sensing ASI neurons to inhibit L2d formation. Moreover, we find that CRH-1 directly binds upstream of the daf-7 TGF-β locus and promotes its expression in the ASI neurons. Taken together, these results provide new insight into how animals alter their developmental programs in response to environmental changes.more » « less
-
Murphy, Coleen T. (Ed.)Many tissue-specific stem cells maintain the ability to produce multiple cell types during long periods of non-division, or quiescence. FOXO transcription factors promote quiescence and stem cell maintenance, but the mechanisms by which FOXO proteins promote multipotency during quiescence are still emerging. The single FOXO ortholog in C . elegans , daf-16 , promotes entry into a quiescent and stress-resistant larval stage called dauer in response to adverse environmental cues. During dauer, stem and progenitor cells maintain or re-establish multipotency to allow normal development to resume after dauer. We find that during dauer, daf-16 /FOXO prevents epidermal stem cells (seam cells) from prematurely adopting differentiated, adult characteristics. In particular, dauer larvae that lack daf-16 misexpress collagens that are normally adult-enriched. Using col-19p :: gfp as an adult cell fate marker, we find that all major daf-16 isoforms contribute to opposing col-19p :: gfp expression during dauer. By contrast, daf-16(0) larvae that undergo non-dauer development do not misexpress col-19p :: gfp . Adult cell fate and the timing of col-19p :: gfp expression are regulated by the heterochronic gene network, including lin-41 and lin-29 . lin-41 encodes an RNA-binding protein orthologous to LIN41/TRIM71 in mammals, and lin-29 encodes a conserved zinc finger transcription factor. In non-dauer development, lin-41 opposes adult cell fate by inhibiting the translation of lin-29 , which directly activates col-19 transcription and promotes adult cell fate. We find that during dauer, lin-41 blocks col-19p :: gfp expression, but surprisingly, lin-29 is not required in this context. Additionally, daf-16 promotes the expression of lin-41 in dauer larvae. The col-19p :: gfp misexpression phenotype observed in dauer larvae with reduced daf-16 requires the downregulation of lin-41 , but does not require lin-29 . Taken together, this work demonstrates a novel role for daf-16 /FOXO as a heterochronic gene that promotes expression of lin-41/ TRIM71 to contribute to multipotent cell fate in a quiescent stem cell model.more » « less
-
Collapsin response mediator protein-2 (CRMP2) in humans, UNC-33 in C. elegans , is a molecule that mediates axonal outgrowth and stability. UNC-33/CRMP2 has been hypothesized as a potential drug target for treating Alzheimer’s and other neurodegenerative diseases, which can often be attributed in part to aging. In aging, CRMP2 becomes hyperphosphorylated, which decreases the protein’s functionality, destabilizes the cellular skeleton, and contributes to neurodegeneration. In C. elegans, aging can be slowed by entering dauer diapause; a non-aging developmental stage turned on when the DAF-7/TGFβ signaling pathway is silenced in response to environmental stressors. In our laboratory, we discovered that unc-33 mutants are unable to form dauers in response to environmental stressors, but the mechanism behind this is still unknown. Here, we present a study that investigates whether a mutation in the daf-7 gene which leads to a temperature sensitive constitutive dauer phenotype can rescue phenotypes characteristic of unc-33 mutants. To this end, we created unc-33 ; daf-7 double mutants and quantified proper dauer formation after exposure to unfavorable environmental conditions. In addition, we tested how the introduction of the daf-7 mutation would affect the locomotion of the double mutants on an agar plate and a liquid medium. Furthermore, we examined axonal elongation of the double mutants using a transgene, juIs76, which expresses GFP in GABAergic motor neurons. Our analysis of unc-33; daf-7 double mutants showed that introducing the daf-7 mutation into an unc-33 mutant rescued dauer formation. However, further studies revealed that the unc-33; daf-7 double mutants had defects in axonal outgrowth of their D-type motor neuron which had been previously seen in unc-33 single mutants and impaired locomotion. Based on these results, we concluded that unc-33 mutants might have a problem suppressing DAF-7 signaling under unfavorable environmental conditions, leading to the activation of reproductive programs and the development of adults instead of dauers.more » « less
- Free Publicly Accessible Full Text
-
Accepted Manuscript1.0
- Journal Article:
- https://doi.org/10.7717/peerj.14713
