BMP Morphogen Gradient Formation, Interpretation, and Signaling Mechanism

Wednesday, March 22, 2023 | 2:00 to 3:00 p.m. ET

Mary Mullins, Ph.D.

Professor of Cell & Developmental Biology, Perlman School of Medicine

University of Pennsylvania

Website

We are studying the molecular mechanisms by which a BMP (Bone Morphogenetic Protein) signal transduction pathway establishes different aspects of the vertebrate body plan. Various zebrafish mutants of BMP pathway components, as well as antisense knockdown approaches are used to dissect the molecular mechanisms by which this pathway establishes different cell types. We are studying the formation, function, and temporal regulation of a BMP activity gradient, which is implicated in specification of diverse cell types along the dorsal-ventral axis. We have shown that this gradient is essential in neural crest specification and is linked to dorsal-ventral patterning of neural tissue. Moreover, a subset of our defined components also function in post-embryonic heart development. Misregulation of BMP signaling leads to a debilitating disease in humans called fibrodysplasia ossificans progressiva (FOP). We are currently trying to establish a model for FOP in the zebrafish.

Summary

Morphogen gradients are a key cell specification mechanism in tissue patterning. How morphogen gradients form and are regulated across space and time is fundamental to proper tissue patterning, yet has been little studied. We investigate BMP morphogen signaling in its conserved role patterning the dorsoventral embryonic axis of vertebrates and invertebrates. We combine experimental studies of BMP antagonists and two metalloproteases in the zebrafish with mathematical modeling and computational screens, which surprisingly countered the decades-long-held counter-gradient model and instead revealed a source-sink paradigm for BMP gradient formation. We further distinguish between three models of BMP morphogen signal interpretation to establish distinct cell fates. Lastly, we investigate the mechanism of the exclusive BMP2-BMP7 heterodimer signaling in embryonic patterning.

Objectives:

*To understand mechanisms of morphogen gradient formation and interpretation.

*To understand the value of computational modeling in deciphering models and generating testable hypotheses.

*To understand the unique properties of BMP heterodimer signaling.