Genetic control of developmental speed in Drosophila // Genetic control of developmental speed in Drosophila

Sorbonne Université SIM (Sciences, Ingénierie, Médecine)
Plein temps Journée complète
Paris

Genetic control of developmental speed in Drosophila // Genetic control of developmental speed in Drosophila






Réf ABG-122173

ADUM-54139


Sujet de Thèse







03/04/2024



Contrat doctoral









Sorbonne Université SIM (Sciences, Ingénierie, Médecine)




Lieu de travail

Paris - France



Intitulé du sujet

Genetic control of developmental speed in Drosophila // Genetic control of developmental speed in Drosophila



Mots clés

Speed of development, Energy metabolism, Drosophila

Speed of development, Energy metabolism, Drosophila






Description du sujet



General background

Decades of research have brought key insights into how size and shape (space) are regulated during animal development. By contrast, much less is known about the speed (time) at which ordered, interacting and non-reversible developmental steps occur during development (Ebisuya and Briscoe, 2018). At the organismal level, developmental speed positively correlates with the rate of metabolism and can be influenced by nutrition and temperature (Gillooly et al., 2002). Additionally, recent studies in closely related mammalian species indicated that developmental speed varied with energy metabolism, mitochondrial activity, global protein stability and/or gene expression (Lázaro et al., 2023; Matsuda et al., 2020)(Diaz-Cuadros et al., 2023)(Iwata et al., 2023)(Rayon et al., 2020). Despite these advances, how developmental speed is regulated remains largely unknown



Preliminary results

Our lab is studying developmental speed in Drosophila, focusing on the speed of developmental patterning in the eye imaginal disc. The adult fly eye develops from an eye primordium that differentiates in a progressive manner as a moving differentiation front, forming a morphogenetic furrow (MF), sweeps through the disc from posterior to anterior. The MF moves at a relatively constant speed over a 2.5 day-period to produce ~30 rows of regularly spaced light-receiving units (Spratford and Kumar, 2015). Its progression involves a self-propagating mechanism (Greenwood and Struhl, 1999)(Fu and Baker, 2003)(Ma et al., 1993)(Roignant and Treisman, 2009). The speed of progression of the MF is a good proxy for developmental speed at the tissue level.

Our lab recently performed a small-scale screen for genes required for the timely progression of the MF. This screen identified several energy metabolism genes, including encoding subunits of the mitochondrial ETC complexes and of the ATP synthase. Using fluorescent sensors for ATP, NAD+ and NADH/NAD+ as well as scRNAseq, we found that loss of ETC activity resulted in increased glycolysis and that this compensatory response was required to maintain ATP constant while promoting NAD+ regeneration. Further analysis identified NAD+ regeneration as a limiting step for developmental speed upon loss of ETC activity. These observations led us to propose that the demand for NAD+ constrained developmental speed in the developing fly eye (Veits et al. in preparation). Thus, our recent work establishes the developing eye of Drosophila as a model system to study the genetic basis of developmental speed.



Questions and aims

Building on our recent findings, the project will aim at identifying the transcription factors (TFs) regulating the change in gene expression associated with the metabolic rewiring induced by ETC inhibition; investigating the role of these TFs in modulating developmental speed in physiological conditions; identifying amongst our positive hits genes that affect developmental speed via a distinct mechanism (i.e. which does not involve a change in ATP/NAD metabolism)



Output

This project addresses a fascinating and largely unexplored question in developmental biology using a novel and powerful model system. The fundamental knowledge generated in this project might shed new light on how the interplay between metabolism, energetic cost of cellular processes operating at a limit for speed







General background

Decades of research have brought key insights into how size and shape (space) are regulated during animal development. By contrast, much less is known about the speed (time) at which ordered, interacting and non-reversible developmental steps occur during development (Ebisuya and Briscoe, 2018). At the organismal level, developmental speed positively correlates with the rate of metabolism and can be influenced by nutrition and temperature (Gillooly et al., 2002). Additionally, recent studies in closely related mammalian species indicated that developmental speed varied with energy metabolism, mitochondrial activity, global protein stability and/or gene expression (Lázaro et al., 2023; Matsuda et al., 2020)(Diaz-Cuadros et al., 2023)(Iwata et al., 2023)(Rayon et al., 2020). Despite these advances, how developmental speed is regulated remains largely unknown



Preliminary results

Our lab is studying developmental speed in Drosophila, focusing on the speed of developmental patterning in the eye imaginal disc. The adult fly eye develops from an eye primordium that differentiates in a progressive manner as a moving differentiation front, forming a morphogenetic furrow (MF), sweeps through the disc from posterior to anterior. The MF moves at a relatively constant speed over a 2.5 day-period to produce ~30 rows of regularly spaced light-receiving units (Spratford and Kumar, 2015). Its progression involves a self-propagating mechanism (Greenwood and Struhl, 1999)(Fu and Baker, 2003)(Ma et al., 1993)(Roignant and Treisman, 2009). The speed of progression of the MF is a good proxy for developmental speed at the tissue level.

Our lab recently performed a small-scale screen for genes required for the timely progression of the MF. This screen identified several energy metabolism genes, including encoding subunits of the mitochondrial ETC complexes and of the ATP synthase. Using fluorescent sensors for ATP, NAD+ and NADH/NAD+ as well as scRNAseq, we found that loss of ETC activity resulted in increased glycolysis and that this compensatory response was required to maintain ATP constant while promoting NAD+ regeneration. Further analysis identified NAD+ regeneration as a limiting step for developmental speed upon loss of ETC activity. These observations led us to propose that the demand for NAD+ constrained developmental speed in the developing fly eye (Veits et al. in preparation). Thus, our recent work establishes the developing eye of Drosophila as a model system to study the genetic basis of developmental speed.



Questions and aims

Building on our recent findings, the project will aim at identifying the transcription factors (TFs) regulating the change in gene expression associated with the metabolic rewiring induced by ETC inhibition; investigating the role of these TFs in modulating developmental speed in physiological conditions; identifying amongst our positive hits genes that affect developmental speed via a distinct mechanism (i.e. which does not involve a change in ATP/NAD metabolism)



Output

This project addresses a fascinating and largely unexplored question in developmental biology using a novel and powerful model system. The fundamental knowledge generated in this project might shed new light on how the interplay between metabolism, energetic cost of cellular processes operating at a limit for speed







Début de la thèse : 01/10/2024

WEB : https://research.pasteur.fr/en/team/4d/




Nature du financement



Contrat doctoral

Précisions sur le financement



Concours pour un contrat doctoral



Présentation établissement et labo d'accueil



Sorbonne Université SIM (Sciences, Ingénierie, Médecine)




Etablissement délivrant le doctorat



Sorbonne Université SIM (Sciences, Ingénierie, Médecine)

Ecole doctorale



515 Complexité du vivant



Profil du candidat



Strong background and interest in cell biology, genetics, metabolism and/or developmental biology

Strong background and interest in cell biology, genetics, metabolism and/or developmental biology


Date limite de candidature

07/06/2024






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