Research
Who runs the world? Morphogens!
Morphogens are extracellular signaling molecules secreted from a localized source that spread into adjacent tissues and direct cell fate decisions in a manner dependent on signaling strength. Essential for metazoan embryogenesis, morphogens control proliferation, differentiation, and patterning during development to orchestrate the formation of tissues and organs. Morphogens have equally important functions in adult tissues, sustaining stem cell homeostasis and promoting regeneration in response to injury. Due to its many roles, morphogen signaling is tightly regulated and even small perturbations in signaling activity can have devastating consequences, resulting in birth defects, cancer, and tissue degeneration.
Mighty Morphogens
Mechanisms underlying signaling sensitivity
Where prior studies focused on understanding how a morphogen’s concentration and duration influence signaling activity, our research focuses on understanding how a receiving cell modulates its sensitivity to a morphogen by regulating the abundance of key receptors at its cell surface.
Our approach has been to utilize a sensitized screening system to identify modulators of morphogen signaling activity (far left), use biochemical and cell biological assays to understand how the protein products of these screen hits regulate signaling sensitivity (middle left), use knockout mouse model systems to understand the role of this regulation in embryonic development (middle right), and finally use all this knowledge to understand the mechanisms that underlie the complex genetics common to many birth defects (far right).
Hedgehog signaling
Currently, our studies focus on the morphogen Sonic Hedgehog. Hedgehog is a core developmental signaling pathway that is essential for the proper growth and patterning of multiple organs including the brain, spinal cord, lungs, heart, and skeleton.
Interested in understanding the mechanisms underlying Hedgehog signaling sensitivity, we initially established a CRISPR-based sensitized screening system adapted with a fluorescent transcriptional reporter to identify modifiers of signaling strength. By isolating cells that were hyper-responsive to a sub-saturating concentration of the morphogen Sonic Hedgehog, we discovered a novel regulatory complex made up of three proteins: MOSMO (a tetraspan), MEGF8 (a single-pass transmembrane protein), and MGRN1 (an E3 ubiquitin ligase). A combination of biochemical and cell biological assays revealed the MOSMO/MEGF8/MGRN1 (MMM) complex is a membrane-tethered ubiquitin ligase complex that regulates a cell’s sensitivity to the morphogen Sonic Hedgehog by controlling the trafficking of the Smoothened (a key transducer of the Hedgehog signaling pathway)to the cell surface
Understanding the design principles of membrane-tethered ubiquitin ligase complexes
Membrane-tethered ubiquitin ligase complexes may represent a major mechanism through which receiving cells control their response to extracellular cues. Using the MMM complex as a model system, we will explore how these systems are regulated and how substrate specificity is achieved.
Major Projects
Identifying mechanisms of signaling sensitivity
Each of the major signaling pathways likely has mechanisms that determine the levels of membrane bound ligands and receptors. Through the use of sensitized screening systems, we will begin to identify the mechanisms that drive sensitivity to other extracellular cues.
Understanding the pathogenesis of hydrocephalus
Obstructive congenital hydrocephalus is a birth defect characterized by a physical blockage of cerebral spinal fluid (CSF) flowing through the ventricular system of the brain. The underlying genetics and molecular pathogenesis of hydrocephalus are poorly understood. Through the use of a cortical spheroid system, we explore how this devastating condition arises from defects in core developmental signaling pathways.