Gebelein Lab

The Notch Signaling Pathway and Embryonic Birth Defects

The Notch signaling pathway provides a basic means of cell-to-cell communication to regulate cell-specific responses during the development of virtually every tissue and organ in our body.

Not surprisingly, dysregulation of the Notch pathway results in complex developmental syndromes and/or diseases that include cancer. In fact, genetic studies have shown that the Notch pathway is highly sensitive to gene dose, which was first discovered in the fruit fly Drosophila melanogaster.

Subsequent studies found that human birth defects and syndromes are linked to both haploinsufficiency and/or dominant genetic variants in three NOTCH receptors (NOTCH1/2/3), four ligands (DLL3/4 and JAG1/2), and the RBPJ transcription factor.

Thus, both Drosophila and vertebrate animal models can be used to understand how Notch pathway dysregulation causes tissue-specific human developmental syndromes.

The Gebelein Lab has two projects on how the Notch pathway is converted into cell-specific responses during development.

  • The first project is a collaboration between Raphael Kopan, MD, PhD and Rhett Kovall, PhD focused on developing and using Drosophila and mouse models of Adams Oliver Syndrome (AOS), a syndrome associated with autosomal dominant NOTCH1 (N1), DLL4, and RBPJ alleles. AOS is defined by scalp aplasia cutis congenita (missing skin and skull tissue) and limb malformations, but patients can also suffer cardiovascular abnormalities, such as cutis marmorata telangiectatica (dilated surface blood vessels), retinal vascularization defects, and heart defects. While it is unclear how N1, DLL4, and RBPJ variants cause the broad spectrum of AOS-associated defects, studies in mice revealed a critical role for N1/Dll4 signaling in endothelial cells during vascular development. Thus, we are testing the hypothesis that defective endothelial signaling could underly each birth defect using a novel mouse model. In addition, we have identified a novel allele in the Drosophila Notch pathway transcription factor (known as Su(H)) that is analogous to a human AOS variant, and we are taking advantage of this novel fly model to define the molecular mechanisms underlying Notch pathway dysregulation.
  • The second Notch project in the Gebelein Lab is a collaboration with David Sprinzak, PhD, a physicist at Tel Aviv University in Israel. In this project, we are combining synthetic biology and mathematical modeling to understand how the Notch pathway is converted into reproducible transcriptional responses. Our basic premise is that if we understand the major components of the Notch pathway, we should be able to predict how specific Notch pathway biosensors respond under a variety of experimental conditions. For example, we have built mathematical models based on our understanding of the pathway, and we use these models to predict how changing the gene dosage of key Notch pathway genes will alter biosensor output. The Gebelein Lab then tests these predictions in flies in which we systematically change Notch pathway gene dose and/or change the number and type of Notch pathway binding sites within the transgenic biosensor reporter. By studying the responses of these biosensors in the presence of dominant disease alleles, we hope to further our understanding of how Notch pathway dysregulation alters gene expression in dose sensitive tissues.