How do organs obtain their final shape during embryonic development?
The cells that make up organs such as your skin, your eyes, and your muscles have to coordinate several different processes in order to adopt their distinctive forms and functions. These processes include 1) modifying cell shape, 2) coordinating cell division, 3) regulating collective migration, and 4) coordinating programmed cell death (apoptosis) to eliminate extraneous or abnormal cells. Dysregulation of any of these processes during embryonic development can have significant consequences on the completed organ, many of which can result in defective function -- which can have dire health implications. Therefore, quality control mechanisms are in place to ensure that organs develop in a stereotyped fashion -- that is, in a way that is highly similar every time, for every embryo. Organ assembly and function therefore requires the coordination of these parameters to maintain a state of homeostasis, or stability in response to external factors.
The fruit fly Drosophila melanogaster has a long and storied history as a favored model organism for investigating fundamental questions in cell biology, developmental biology, genetics, neurobiology, and even cancer biology. 60% of disease-causing genes are conserved between fruit flies and humans, ensuring that many of the insights found via the study of Drosophila have direct implications on human health. The use of flies in research is particularly advantageous due to their short generation time (flies generally live for about 30 days, with embryonic development completing in a span of 24 hours), presence of readily-visible dominant markers, and straightforward genetics. Their ease of use make them an ideal model organism for introducing student researchers to many different fields of biology.
The Drosophila midgut muscles are required for the peristaltic movement of food through the digestive tract in larvae. These muscles form during embryogenesis via the synchronous bilateral collective migration of a population of muscle precursor cells at the tail-most end of the embryo called caudal visceral mesoderm (CVM). These CVM cells move along another population of muscle precursor cells called trunk visceral mesoderm (TVM), which serve as a 'track' for the CVM cells. The CVM cells migrate along the TVM over a span of six hours, which is the longest migration of any cell type in the developing embryo. At the conclusion of their migration, the CVM cells fuse with fusion-competent myoblasts in the TVM, forming the multinucleate muscle fibers that surround the midgut.
The Macabenta Lab seeks to uncover new mechanisms for how these CVM cells are able to accomplish this collective migration, as well as account for the elimination of cells that are deemed unfit to contribute to the completed muscle system via apoptosis (programmed cell death). As such, we have three different projects aimed at identifying different aspects of CVM behavior:
Diagrams (left) and immunostained Drosophila embryos (right) showing CVM cell (red) migration over time along TVM track (cyan). Reproduced from Macabenta and Stathopoulos 2019.
Project 1: Interdependent tissue dynamics during collective migration
CVM cells encounter multiple other cell types during their long migration. How do these other cells influence the migration of the CVM, and what molecular signals do they use to influence the CVM?
Project 2: MicroRNA-dependent quality control during organ development
MicroRNAs are known for their roles in gene regulation and cancer pathology. We recently uncovered a quality control mechanism that eliminates abnormal CVM cells, and are investigating how microRNAs might be involved in this process.
Project 3: Nonapoptotic roles of caspases
Caspases are enzymes most well known for initiating programmed cell death in response to a signaling cascade. However, new research has found that they can have functions beyond promoting cell death. We are interested in determining if caspases have a role in patterning muscles in fly embryos.