Sarah Knox, PhD

The Knox lab is concerned with analyzing the cellular and molecular events underlying the formation of epithelial organs (organogenesis) and their regeneration after injury. We employ tissues such as the salivary and lacrimal glands, as well as the prostate and pancreas and epithelial organs of the eye to discover key regulators governing organ architecture. Many of these organs form by the conserved process of branching morphogenesis, in which a single epithelial stalk arborizes into an elaborate interconnected tubular network through which liquids are transported. For each tissue, morphogenesis is governed by a diverse set of cell to cell and cell to extracellular matrix interactions. For example, salivary gland epithelial cells not only interact with the surrounding mesenchymal cells, which provide essential growth factors such as FGF10, but also with endothelial, immune and neuronal cells during development and regeneration. However, the role of these latter cell-cell interactions in organogenesis and repair is poorly understood.

It was previously assumed that the peripheral nervous system had no role during embryogenesis, despite it being necessary for tissue homeostasis in the adult. Our recent work has demonstrated that neuronal-epithelial communication is essential for maintaining epithelial progenitor cells in the developing and adult salivary gland and prostate through the acetylcholine/muscarinic/EGFR signaling network. In the absence of innervation and thus neurotransmitter release, the pool of undifferentiated progenitors is reduced, inhibiting tissue development and regeneration. In our current studies we aim to decipher the mechanisms by which nerves regulate organ architecture, control stem cell fate and modulate regeneration through interactions with the immune system. As such, we are in the process of testing three fundamental biological questions:

1. How does innervation impact epithelial stem cell fate decisions?
2. What are the mechanisms by which neuronal signals pattern organ architecture?
3. How do immune cells modulate nerve-mediated morphogenesis, repair and regeneration?

To answer these questions, we utilize novel integrative approaches based on ex vivo and in vivo systems, mouse genetics, human fetal development, bioinformatics and patient samples. Lastly, by employing a multi-organ approach and interspecies tissues (mouse and human), we enhance the power of discovery of general mechanisms required for these processes.

In sum, understanding the relationships between multiple cell types (stem cells and differentiated cells included) within organ systems is essential if we are to regenerate or generate these tissues in the advent of organ failure.