We are interested in understanding how Notch signaling affects cell differentiation processes and how dysregulated Notch signaling leads to disease. Furthermore, we want to understand the molecular underpinnings of the different steps in the Notch signaling cascade, and how a pathway with a relatively simple molecular architecture can generate a wide variety of cell context-dependent signaling outputs.
1. Exploring the role of Notch in cellular differentiation
We study the role of Notch in various cell lineage progressions, in the neural, hematopoietic and vascular systems, as well as in heart and liver development. In the vascular system, we explore why Notch signaling induces arterial rather than venous fates both in the endothelium and in mural cells and how Notch affects the phenotypic plasticity of vascular smooth muscle cells. In liver development, we address how the choice between bile duct cells and hepatocytes is controlled by Notch. We are interested in common and specific principles for how Notch can instruct cell fate decisions in a broad variety of cell contexts, and how this functional diversity correlates with diversity in downstream signaling output. A focus of the laboratory is also on how the temporal cell context during progression through a particular cell lineage influences Notch signaling, leading to various signaling outputs appropriate for each decision point in a cell lineage.
2. Understanding the role of dysregulated Notch signaling in disease
Dysregulated Notch signaling is increasingly linked to various disease conditions. We focus on the role of Notch signaling in breast cancer, where Notch is rarely mutated but frequently upregulated. We have recently unraveled a link between dysregulated Notch signaling and the cellular metabolic state, and we are currently exploring how Notch affects tumor-stroma interactions and the cytokine response in breast cancer. We are also interested in understanding the molecular basis for the profound differences in immediate Notch transcriptomes from various types of breast cancers and how they may reflect various molecular and epigenetic states in breast cancer.
In another project, we assess the role of the Notch3 receptor in vascular biology, with a particular focus on vascular smooth muscle cells. In humans, mutations in NOTCH3 lead to the stroke and dementia syndrome CADASIL, and we explore the effects of NOTCH3 loss-of-function in the mouse. As Notch signaling also plays a role in pulmonary arterial hypertension (PAH), we are interested in addressing how phenotypic modulation of vascular smooth muscle cells between contractile and synthetic phenotypes are regulated by Notch.
We are currently also exploring how dysregulated Notch ligand (JAGGED1) function leads to the multi-organ disease Alagille syndrome. The majority of Alagille patients carry JAGGED1 mutations, and we have recently developed mouse models which closely mimic Alagille pathologies in various organs.
Finally, we are interested in gaining new insights into how Notch-related toxicology can be avoided when gamma-secretase inhibitors and modulators are explored for potential therapies to Alzheimer’s disease. We are addressing to what extent different types of gamma-secretase complexes exert different effects on Notch receptor processing, as compared to processing of the amyloid precursor protein.
3. Dissecting the Notch signaling cascade
The core Notch signaling cascade has a rather simple molecular architecture, but generates very diverse downstream signaling outputs, depending on the cell context. We study how distinct steps in the signaling cascade are modulated, and how auxiliary proteins impinge on Notch signaling. Over the years we have analyzed how ubiquitylation controls longevity of the Notch intracellular domain, and how the Notch signaling cascade interacts with other signaling pathways, notably BMP/TGFbeta signaling and the cellular hypoxic response. We have established that the Notch intracellular domain is an interaction hub, and can interact with SMAD proteins in the BMP/TGFbeta pathways as well as with HIF1alpha and FIH in the cellular hypoxic response. More recently, we have also unraveled a link between Notch and the PI3 kinase and NF-kB signaling pathways, and we address how Notch signaling modulates the signaling output from these pathways. Another line of research aims at identifying novel proteins that modify Notch signaling output. Here, we are in the process of identifying kinases that act on the Notch intracellular domain.
Tools used in the laboratory
To address these topics, we use a variety of experimental techniques. We use genetically engineered mice, both to ablate Notch signaling and to induce Notch gain-of-function effects in a tissue-specific manner. We have developed various Notch reporter constructs, including reporters for in vivo use, and currently generate tools to explore which proteins interact with the Notch transcription complex and how the transcription complex accesses DNA at the genome-wide level. We have also developed a broad portfolio of gain- and loss-of-function constructs for analysis of Notch signaling in vitro (see published work for specific antibodies and DNA-constructs).
Long term vision
We hope that our research will lead to a better understanding of the Notch signaling pathway and contribute to understanding its specific roles in various tissues and cell types. We also hope that these endeavors will contribute to deciphering why dysregulated Notch signaling leads to various forms of disease. Long term, we hope to find ways to remedy the effects of a mal-functioning Notch cascade to improve human health, and to develop strategies to eliminate effects of Notch toxicity as an unwanted side effect from pharmaceutical intervention with other disease processes.