The BMP2/4 ortholog Dpp functions as an inter-organ signal that regulates developmental timing in<i>Drosophila</i>

Setiawan, Linda; Woods, Alexis L; Hariharan, Iswar K.

doi:10.1101/180562

Cited by 4 publications

(3 citation statements)

References 37 publications

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“…Aside from local signaling, Dpp also regulates developmental timing. Dpp acts in the prothoracic gland to suppress ecdysone release by repressing the expression of genes required for ecdysteroidogenesis ( Setiawan et al 2017 ). It is possible defects in Dpp signaling in the prothoracic gland of Pngl mutants could cause the misregulation of ecdysone production.…”

Section: Discussionmentioning

confidence: 99%

Defects in the Neuroendocrine Axis Contribute to Global Development Delay in a Drosophila Model of NGLY1 Deficiency

Rodriguez

Mast

Hartl

et al. 2018

G3 Genes|Genomes|Genetics

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N-glycanase 1 (NGLY1) Deficiency is a rare monogenic multi-system disorder first described in 2014. NGLY1 is evolutionarily conserved in model organisms. Here we conducted a natural history study and chemical-modifier screen on the Drosophila melanogaster NGLY1 homolog, Pngl. We generated a new fly model of NGLY1 Deficiency, engineered with a nonsense mutation in Pngl at codon 420 that results in a truncation of the C-terminal carbohydrate-binding PAW domain. Homozygous mutant animals exhibit global development delay, pupal lethality and small body size as adults. We developed a 96-well-plate, image-based, quantitative assay of Drosophila larval size for use in a screen of the 2,650-member Microsource Spectrum compound library of FDA approved drugs, bioactive tool compounds, and natural products. We found that the cholesterol-derived ecdysteroid molting hormone 20-hydroxyecdysone (20E) partially rescued the global developmental delay in mutant homozygotes. Targeted expression of a human NGLY1 transgene to tissues involved in ecdysteroidogenesis, e.g., prothoracic gland, also partially rescues global developmental delay in mutant homozygotes. Finally, the proteasome inhibitor bortezomib is a potent enhancer of global developmental delay in our fly model, evidence of a defective proteasome “bounce-back” response that is also observed in nematode and cellular models of NGLY1 Deficiency. Together, these results demonstrate the therapeutic relevance of a new fly model of NGLY1 Deficiency for drug discovery and gene modifier screens.

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Section: Discussionmentioning

confidence: 99%

Defects in the Neuroendocrine Axis Contribute to Global Development Delay in a Drosophila Model of NGLY1 Deficiency

Rodriguez

Mast

Hartl

et al. 2018

G3 Genes|Genomes|Genetics

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“…Although Activin signaling is typically thought to be a short-range signaling pathway, TGFb ligands can act systemically (Upadhyay et al, 2017). For example, it was recently shown in Drosophila that the BMP ligand Dpp, emanating from larval imaginal discs, acts as a developmental timer: as the animal grows, systemic Dpp is trapped by larger tissues, which is sensed by the ecdysone releasing organ to regulate entry into metamorphosis (Setiawan et al, 2018). The potential importance of local and/or systemic Activin ligands and how they might affect neuronal diversity and temporal patterning will be the topic of future investigations.…”

Section: Local or Systemic Activin Ligand(s) Could Act On Mushroom Bomentioning

confidence: 99%

Extrinsic Activin signaling cooperates with an intrinsic temporal program to increase mushroom body neuronal diversity

Rossi

Desplan

2019

Preprint

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How diverse neuronal types are sequentially generated from individual neural stem cells is a central question in neurobiology. This "temporal patterning" is controlled by both intrinsic and extrinsic cues. Whether and how extrinsic cues interact with intrinsic programs to increase neuronal diversity, or if they only fine-tune the timing of temporal transitions, is not known. We use the simple Drosophila mushroom body lineage, comprised of only three neuronal types that are sequentially produced, to address the role of extrinsic cues in temporal patterning. As they age, mushroom body stem cells (neuroblasts) advance through intrinsic and opposing temporal gradients of two RNA-binding proteins, Imp and Syp. These intrinsic gradients are used to first produce g, then a'b', and finally ab neurons. The specification of each neuronal type is temporally confined to specific developing stages, and progression from one temporal window to the next occurs concurrently with key, developmental events. This suggests that extrinsic cues play important roles in patterning temporal identity in this lineage. We show that an extrinsic cue, Activin, not only times the young (Imp) to old (Syp) neuroblast fate transition but that it is also essential for increasing neuronal diversity by defining the mid-temporal window (a'b'). Activin reduces the levels of the intrinsic factor Imp, creating a scenario where Imp and Syp are both at low levels for an extended period. In Activin receptor mutants, a'b' neurons are not generated because high Imp levels inhibit the activation of a'b' effectors, including ecdysone receptor signaling.Additionally, the g temporal window appears to be extended and the ab window is shortened, due to a delayed Imp to Syp transition. Our results illustrate that temporal extrinsic cues during neurogenesis can modify an intrinsic temporal program to increase neuronal diversity.

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“…It has also been argued that slow growth compensation in response to growth perturbation is related to low levels of the steroid hormone ecdysone [17, 18, 128]. Others argue that dynamic stabilization of growth against perturbations requires multiple adjustments of growth hormones, maturation hormones and growth regulators [16, 153, 144, 153–155].…”

Section: Sensing Perturbations Damage and Fitness In Growing Organsmentioning

confidence: 99%

Systemic signalling and local effectors in developmental stability, body symmetry, and size

Juarez-Carreño¹,

Morante²,

Domı́nguez³

2018

CST

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Symmetric growth and the origins of fluctuating asymmetry are unresolved phenomena of biology. Small, and sometimes noticeable, deviations from perfect bilateral symmetry reflect the vulnerability of development to perturbations. The degree of asymmetry is related to the magnitude of the perturbations and the ability of an individual to cope with them. As the left and right sides of an individual were presumed to be genetically identical, deviations of symmetry were traditionally attributed to non-genetic effects such as environmental and developmental noise. In this review, we draw attention to other possible sources of variability, especially to somatic mutations and transposons. Mutations are a major source of phenotypic variability and recent genomic data have highlighted somatic mutations as ubiquitous, even in phenotypically normal individuals. We discuss the importance of factors that are responsible for buffering and stabilizing the genome and for maintaining size robustness and quality through elimination of less-fit or damaged cells. However, the important question that arises from these studies is whether this self-correcting capacity and intrinsic organ size controls are sufficient to explain how symmetric structures can reach an identical size and shape. Indeed, recent discoveries in the fruit fly have uncovered a conserved hormone of the insulin/IGF/relaxin family, Dilp8, that is responsible for stabilizing body size and symmetry in the face of growth perturbations. Dilp8 alarm signals periphery growth status to the brain, where it acts on its receptor Lgr3. Loss of Dilp8-Lgr3 signaling renders flies incapable of detecting growth perturbations and thus maintaining a stable size and symmetry. These findings help to understand how size and symmetry of somatic tissues remain undeterred in noisy environments, after injury or illnesses, and in the presence of accumulated somatic mutations.

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The BMP2/4 ortholog Dpp functions as an inter-organ signal that regulates developmental timing inDrosophila

Cited by 4 publications

References 37 publications

Defects in the Neuroendocrine Axis Contribute to Global Development Delay in a Drosophila Model of NGLY1 Deficiency

Defects in the Neuroendocrine Axis Contribute to Global Development Delay in a Drosophila Model of NGLY1 Deficiency

Extrinsic Activin signaling cooperates with an intrinsic temporal program to increase mushroom body neuronal diversity

Systemic signalling and local effectors in developmental stability, body symmetry, and size

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