Friday, May 9, 2025
5/9/2025
Linking systemic and local signaling for proportional growth - Proportional growth ensures overall size is coordinated with organ and limb size to generate the correct animal body form. In all animals, body size is determined by a plastic response to environmental factors such as nutrition. The TOR pathway senses amino acids and, together with the insulin pathway and hormones, regulates growth to produce an overall size best suited for the conditions, such as a small organism if food is limiting. Local growth of organs and limbs is more autonomous and robust so that the final structure is correctly patterned while scaled for overall body size. For example, fly wings of different sizes have the same stereotypical pattern of veins, intervein regions, and sense organs needed to produce a functional wing. The long-term goal of this project is to understand how systemic signaling and local growth are coordinated in the gene regulatory network (GRN) for Drosophila wing development. The goal for this proposal is to investigate the first circuit in the GRN when it is hypothesized that a systemic signal activates local growth pathways to induce the first cell divisions in the nascent wing disc. The fly wing is a flagship model for analyzing signaling and appendage growth and patterning; however, there is a gap in knowledge about the earliest stage of wing disc development. This stage is poorly understood because the tiny disc is comprised of only approximately 30 cells. Expertise in handling the small samples, exemplified in preliminary data, show size is not a barrier to gaining mechanistic insights into the nature of the systemic signal and determining which local growth pathways are sensitive to it. In Aim 1, experiments will test the hypothesis that insulin signaling is the systemic input that stimulates wing cell growth and activates a morphogenetic pathway(s) to initiate the cell cycle. Genetic manipulation, antibody staining, and imaging will be used to determine if modulation of insulin signaling regulates cell cycle dynamics in the wing disc. In Aim 2, the target pathway(s) of the systemic signal will be identified. The pathways under investigation are the major growth and morphogenetic pathways; Dpp, Wingless, Egfr, Hedgehog, and Notch, which are required for correct patterning and growth of the wing disc. Pathway markers and targets will be used to monitor activity in starved and fed larvae. Pathways that are sensitive to nutrition for activation are candidates for response to the systemic signal. The role of these pathways in cell cycle initiation will be determined by using genetics to activate or repress a given pathway followed by assaying the cell cycle. Preliminary data show that Egfr activity is sensitive to nutrition and required for cell cycle progression. The results strongly support feasibility of the approach but leave open the question of how direct the link is between the Egfr pathway and the systemic signal. In the last part of Aim 2, the interrelationships of the morphogenetic pathway to each other and to the systemic signal will be analyzed. As well as being a fundamental question in development, proportional growth also has health and wellness implications. Altered body forms can lead to stigmatization, influence susceptibility to disease, and in the case of limb abnormalities, occur in 1/1900 births.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).