# Investigations of the molecular genetics and pathogenesis of scoliosis.

> **NIH NIH R01** · UNIVERSITY OF TEXAS AT AUSTIN · 2024 · $449,098

## Abstract

ABSTRACT
This is a renewal application of an established program to investigate the regulation of the development and
homeostasis of the spine. During the first funding period, our studies demonstrated that the gene Adgrg6,
implicated in a common human spine disorder called adolescent idiopathic scoliosis, has an essential role in
maintaining spine alignment in mice. We showed that the G-protein coupled rector Adgrg6 regulates gene
expression and biomechanical properties of the intervertebral discs and dense connective tissue of the spine.
Furthermore, we demonstrated that Adgrg6 stimulates cAMP signaling regulate factors essential for
homeostasis of fibrocartilaginous tissue of the spine. Our findings suggest a new hypothesis that stimulation
of cAMP signaling can decrease the onset and severity of scoliosis caused by the loss of Adgrg6
signaling. In addition, human genetics analysis of scoliosis identified a novel variant located in the
transcriptional activation domain of the transcription factor SOX9. Significantly, targeted disruption of this
domain of Sox9 in mice caused scoliosis and dysregulation of gene expression in fibrocartilaginous tissues of
the spine. Here, we will test the hypothesis that Adgrg6 and Sox9 are functionally linked for regulation
homeostasis and alignment of the spine.
 To add breadth to our program goals, we continued a forward genetic screen to isolate a collection of
spine disorder mutant zebrafish. We recently identified two zebrafish mutants that fail to complement a novel
thoracic scoliosis phenotype, suggesting a new pathway controlling spine morphogenesis. The characterization
of this unique thoracic scoliosis phenotype will expand our knowledge into the cellular and molecular
heterogeneity of spine disorders. Here, we will test the hypothesis that thoracic scoliosis in zebrafish is
caused by a disruption of purinergic signaling leading to defects in notochord biogenesis.
 We will test these hypotheses via studies divided into three Specific Aims. Specific Aim 1 will deepen
our mechanistic understanding of effectors of Adgrg6 signaling in the spine and test whether stimulation of
cAMP can restore homeostasis to fibrocartilaginous tissues of the spine and halt the onset and progression of
scoliosis. Specific Aim 2 will characterize the cellular and molecular causes of scoliosis in a novel Sox9 mutant
mouse and use this model to test whether genetic interactions between Adgrg6 and Sox9 variants increase the
susceptibility to scoliosis. Specific Aim 3 will characterize novel thoracic scoliosis mutant zebrafish and test a
model that purinergic signaling is essential for notochord biogenesis and spine morphogenesis in zebrafish.
Our results will provide new insights into the molecular genetics and biological processes necessary for the
development and homeostasis of the spine. These studies may provide fundamental insights into the biological
processes and pathways associated with human skeletal dysplasia and scoli...

## Key facts

- **NIH application ID:** 10771257
- **Project number:** 5R01AR072009-07
- **Recipient organization:** UNIVERSITY OF TEXAS AT AUSTIN
- **Principal Investigator:** Ryan Scott Gray
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $449,098
- **Award type:** 5
- **Project period:** 2017-07-10 → 2027-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10771257

## Citation

> US National Institutes of Health, RePORTER application 10771257, Investigations of the molecular genetics and pathogenesis of scoliosis. (5R01AR072009-07). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10771257. Licensed CC0.

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