# Role of Energy Metabolism in Patterning the Vertebrate Musculo-Skeletal Axis

> **NIH NIH R01** · BRIGHAM AND WOMEN'S HOSPITAL · 2021 · $670,072

## Abstract

Project Summary/Abstract
The proposed project is focused on the crosstalk between metabolism and cell fate during development of the
paraxial mesoderm, the tissue which forms skeletal muscles and vertebrae. One striking characteristic of this
tissue is its segmentation into repeated structures termed somites, a process driven by a molecular oscillator
called segmentation clock [1]. Defects in paraxial mesoderm development can lead to severe malformations
such as congenital scoliosis, spina bifida or caudal agenesis. The paraxial mesoderm arises from a population
of progenitors located in the primitive streak and tail bud. Remarkably, these progenitor cells exhibit aerobic
glycolysis and an inverted intra- vs. extracellular pH gradient, which are characteristic of the Warburg effect of
cancer cells [2, 3]. In the tailbud, we demonstrated that glycolysis increases the intracellular pH to promote
acetylation of -catenin and Wnt activation, which ultimately leads to paraxial mesoderm induction [3]. As these
processes are difficult to study in vivo, we have developed in vitro systems in which embryonic stem (ES) cells
or induced pluripotent stem (iPS) cells can be efficiently differentiated toward the paraxial mesoderm fate
recapitulating the normal features of its metabolism, signaling and even oscillations of the segmentation clock
[4-7]. We will now take advantage of these in vitro systems, as well as mouse and chicken embryos, to
characterize in detail the role of aerobic glycolysis in paraxial mesoderm development to see how it relates to
the Warburg effect. In this application, we propose to carry out large scale multi-omics experiments
(metabolomics, transcriptomics, proteomics, epigenomics) and live imaging of cellular metabolic state to
characterize the impact of metabolic transitions on the regulation of gene expression, protein function and cell
fate. As the physiological significance of the Warburg effect is not well understood, carefully dissecting its role
in the embryo might help shed light on its role in cancer. Finally, we propose to use in vivo, ex vivo and in vitro
systems recapitulating the oscillations of the segmentation clock to study the role of metabolism in the control
of the oscillatory period. We will analyze the differences in metabolism regulation between mouse and human
paraxial mesoderm cells, with special focus on mitochondrial respiration. The period of the oscillations diverges
significantly between the two species and can be used as a proxy for developmental timing to try to understand
why human development proceeds more slowly than mouse development. We expect these experiments to
shed light on the molecular basis of developmental timing, which is tightly linked to longevity in mammals.

## Key facts

- **NIH application ID:** 10211585
- **Project number:** 2R01HD085121-06A1
- **Recipient organization:** BRIGHAM AND WOMEN'S HOSPITAL
- **Principal Investigator:** OLIVIER POURQUIE
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $670,072
- **Award type:** 2
- **Project period:** 2016-03-01 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10211585

## Citation

> US National Institutes of Health, RePORTER application 10211585, Role of Energy Metabolism in Patterning the Vertebrate Musculo-Skeletal Axis (2R01HD085121-06A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10211585. Licensed CC0.

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