David Walterhouse, MD, a pediatric oncologist with an international reputation for the treatment of childhood sarcomas, works closely with Philip Iannaccone, MD, PhD on the role the GLI genes play in both cancer and early developmental fate decisions. Together with Joon Won Yoon, PhD, we focus on the genetic regulation and biochemical mechanisms of action of a family of transcription factors identified in human brain tumors (glioblastoma) and subsequently shown to be very similar in sequence structure and function to genes in the fruit fly, mouse and roundworm, indicating the fundamental importance of the genes.
We study the network of Sonic Hedgehog (Shh) and GLI genes, a critical developmental signal transduction pathway because of its potential implications for human health. In this network, the protein Shh functions as a signal outside of the cell, interacting with receptors on the surface of the cell, which cause a series of intracellular events. A cascade of changes in the molecule GLI inside the cell at a specialized structure called the primary cilium leads to movement of GLI into the nucleus where it interacts with the genes that it regulates. We have studied how GLI functions as a “molecular switch” that turns other genes on and off. The Shh/GLI network is responsible for a wide variety of serious birth defects or cancer when there are mutations in the GLI gene that disrupt its interaction with target genes and interfere with its regulatory function.
There are important implications of these studies to evolutionary development. Shh and GLI are known to be conserved from the roundworm to human beings. This degree of conservation implies that these genes are likely highly conserved in structure, process, and function and are thus critical to the species and important in the study of evolutionary development. Advancing our understanding of these structures and processes is fundamental to understanding evolutionary development as it relates to human health.
The lab has devoted much attention to the mechanism of stem cell allocation to organs as they develop. We have used genetic mosaics and chimeras to follow allocation and movement of cells in a variety of organs including liver, adrenal cortex and cornea. We have established that algorithmic growth can explain the observed patterns of allocation and that the process is fractal, consistent with iterative division rules that can be self-organizing. This work will help develop paradigms to assess the quality of tissue engineering products. This work has been published in PLoS One.