# Regulatory Mechanisms Governing Precision in Vertebral Segmentation

> **NIH NIH R35** · CINCINNATI CHILDRENS HOSP MED CTR · 2024 · $1

## Abstract

PROJECT SUMMARY/ABSTRACT
 The timely and precise progression of a genetic program along a cascade of regulatory steps is critical to
execute a developmental process. However, gene expression is a highly stochastic process due to inevitable
fluctuations in the kinetics of complex biochemical reactions; this randomness leads to substantial cell-to-cell
variability (gene expression noise). The resulting phenotypic fluctuations can only be detected and quantified at
the single cell level within isogenic populations. One of the most intriguing questions in science is how
developmental pattern formation is executed so precisely and reproducibly despite these unavoidable
fluctuations in gene expression. Presumably, mechanisms that buffer stochastic gene expression must exist.
 Vertebrate somitogenesis provides a paradigm system for studying this question. Somite segments (the
embryonic precursors of vertebrae) are produced sequentially and periodically from the presomitic mesoderm
(PSM) at the tail end of the embryo. The period of somite segmentation is controlled by the segmentation
clock. The segmentation clock exhibits oscillatory expression of Hes/her-family “clock” genes due to an
autoinhibitory intracellular negative feedback loop. Oscillating Delta ligands activate Notch receptors in
neighboring cells and establish an intercellular positive feedback loop that synchronizes oscillation phases
among neighboring cells. Disruption of these synchronized oscillations results in birth defects. The time-course
of somite segmentation and epithelization occur along the posteroanterior direction in the PSM. The
coordinated expression of multiple genes along the PSM are controlled by three interconnected signaling
gradients (Fgf, Wnt and retinoic acid). Somitogenesis is both precise – embryos of a given species develop
certain number of segments with species-specific rhythmicity – and versatile –total number of segments and
their periodicity vary widely among species. Somitogenesis is also robust as embryos form segments with a
certain size distribution, scaling the sizes of segments with body size, even when total cell numbers, cell sizes
or growth rates are altered experimentally. These characteristics indicate that the expression noise within the
oscillating segmentation network is efficiently buffered.
 Our overarching goal is to decipher how expression noise in gene regulatory networks is buffered during
developmental pattern formation. We aspire to reach a mechanistic understanding of this buffering by
combining mathematical/computational/statistical modeling with different genetic and chemical perturbations to
modify dosage of multiple genes or modulate signal feedback strength.

## Key facts

- **NIH application ID:** 10812486
- **Project number:** 5R35GM140805-04
- **Recipient organization:** CINCINNATI CHILDRENS HOSP MED CTR
- **Principal Investigator:** Ertugrul M Ozbudak
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $1
- **Award type:** 5
- **Project period:** 2021-06-01 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10812486

## Citation

> US National Institutes of Health, RePORTER application 10812486, Regulatory Mechanisms Governing Precision in Vertebral Segmentation (5R35GM140805-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10812486. Licensed CC0.

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