Identifying developmental pathways that regulate bilateral growth symmetry

NIH RePORTER · NIH · R21 · $242,250 · view on reporter.nih.gov ↗

Abstract

Abstract Growth is a fundamental property of animal development. While research has uncovered many of the molecular pathways responsible for regulating tissue size, how the activity of those pathways is coordinated across different organs or tissues to produce the proportion and symmetry we observe in mature tissues remains a mystery. In this proposal, we generate an experimental model that will serve as a basis for exploring symmetric growth coordination (SGC) between paired tissues in the fruit fly Drosophila melanogaster, a genetically tractable developmental model. In Drosophila, adult appendages derive from larval tissues called imaginal discs. During larval development, damaged imaginal discs can regenerate. In previous work, my research group described how release of the relaxin hormone Dilp8 by regenerating tissues, and the activation of the Dilp8 receptor Lgr3 in the brain and endocrine tissues, coordinates the growth of regenerating and undamaged tissues to maintain appropriate adult proportion. Loss of Dilp8/Lgr3 signaling also produces an increased frequency of spontaneous growth asymmetries in the wings of mutant animals. However, the low penetrance of this phenotype makes it difficult to examine how SGC is regulated during development. To overcome this experimental difficulty, in this proposal we describe a new genetic model to look at SGC between paired tissues, such as Drosophila wings. Since male and female wings have different growth rates, bilateral sexual mosaics, or gynandromorphs, allow us to determine whether compensatory growth pathways are activated in response to growth asymmetries. Using this genetic model, our preliminary data reveals that there is growth coordination between male and female tissues in gynandromorphs. We also observe that gynandromorph development is delayed and that both male and female tissues are smaller. Both of these phenotypes are consistent with the activation of the Dilp8/Lgr3 pathway in gynandromorphs. Therefore, we propose genetic approaches to test the role of Dilp8/Lgr3 pathway in mediating SGC in gynandromorphs. Additionally, by developing a fluorescent reporter for identifying larval gynandromorphs, we will determine the developmental stages where SGC occurs and identify gene expression patterns associated with slower and faster growing tissues during growth compensation. Developmental growth compensation during early human development is associated with higher risk of long-term heath complications, including metabolic and cardiovascular disease. By examining SGC in our model, we hope to gain insights into the etiology of these compensation-induced disease states to direct clinical research towards new therapies.

Key facts

NIH application ID
10131235
Project number
5R21HD101785-02
Recipient
UNIVERSITY OF VIRGINIA
Principal Investigator
ADRIAN J HALME
Activity code
R21
Funding institute
NIH
Fiscal year
2021
Award amount
$242,250
Award type
5
Project period
2020-04-01 → 2024-03-31