Matthew Scott, Ph.D.

Professor of Developmental Biology and Genetics

Investigator of the Howard Hughes Medical Institute

Early embryonic development is governed by an exquisite interplay of genes that organizes cells as they proliferate. Signals flow between cells to control their fates; information inherited by the cells influences their responses to the signals. Much of the genetic machinery that builds the embryo is ancient. Transcription factors necessary for forming particular parts of the body, such as head-to-tail differences, hearts, eyes, or nervous system, have remained dedicated to those tasks through evolution. Similarly, the genes and proteins that code for signals, signal receptors, and information transfer within the cell have been preserved, as have many of the relationships among them. Using Drosophila and mice, we study evolutionarily conserved regulators to learn how the embryo is constructed and how pattern-organizing genetic programs arose, function, and change.

We work on signaling systems used in development, particularly the Hedgehog (Hh) signaling pathway. Many of the components of the Hh pathway were discovered first as segmentation genes that affect early embryonic development in the fly Drosophila. Defects in Hh signaling cause the pattern of body segmentation to change: cells in particular locations make inappropriate decisions about what structures to make. The genes are also active during leg and wing development and in the muscles, nervous system, and a wide variety of organs. Mutations of the corresponding genes in mice cause major patterning defects in multiple organs. We have investigated one of the segmentation genes, patched (ptc), which encodes a receptor protein to which Hh signal binds.

We identified mouse and human ptc genes, and showed that reduction or elimination of ptc1 function during mouse development leads to spina bifida, polydactyly, midbrain overgrowth, failure to form dorsal neural tube cell fates, defects in the heart and aorta, excessive body size, and other problems that we continue to investigate. We found that mutations in human PATCHED (PTCH) are inherited in families with the basal cell nevus syndrome. These individuals exhibit a variety of birth defects and often develop medulloblastoma of the cerebellum and basal cell carcinoma of the skin, the most common human cancer. We confirmed the involvement of PTCH in these tumors by looking for mutations in sporadic cases of the disease and by constructing mouse models of both cancers, using knowledge of the signaling pathway derived from studies in flies. We are using the mouse models to investigate changes that occur in the conversion of normal cells to tumor cells. The role of PTCH in medulloblastoma suggested a role for Shh signaling in normal cerebellar development. We found that Hh is a powerful inducer of cell division for the major type of cerebellar neuron. We are continuing to study the mechanisms and impact of Shh signaling in the cerebellum. With retroviral infections we trace migrations of cerebellar cells and manipulate genes that may affect those migrations. cDNA microarrays are being applied to discover other genes required for cerebellar development.

The protein most closely related to Ptc was first identified as the protein mutated in the human syndrome Niemann-Pick type C1 (NPC1), a neurodegenerative disease. There are also other connections between lipid trafficking and Hh signaling. NPC1 is required for normal transport of cholesterol and other lipids between cell organelles, and we have studied which organelle trafficking events depend upon NPC1. We are investigating functions of NPC1 protein, as well as the transduction of Hh signals by its relative Ptc. Many mysteries remain about how a Hh signal is interpreted by the cellular machinery. One gene necessary for repression of Hh target genes in flies is costal2, which we found encodes a putative motor protein that may transport organelles within cells. We are studying Costal 2 protein functions and structure, in particular its associations with other Hh signaling molecules, to learn its molecular role in transport and Hh signal transduction.

The completion of the Drosophila genome sequence has made it possible to study the activation of all genes during the entire life cycle. Our lab has collaborated with those of Mark Krasnow, Bruce Baker, Ron Davis, all at Stanford, and Kevin White, now at Yale, to determine the patterns of gene transcription during all of development. A special value of doing such analyses in Drosophila is that nearly a century of research has produced thousands of mutants that can be used to link gene functions to developmental events. To facilitate such analyses, we have built an instrument that allows the separation of large quantities of mutant embryos from normal embryos. The mutant embryos can then be analyzed for their gene expression patterns or used for biochemical experiments. We have applied this system to the analysis of mutants that lack all muscles, or that are composed entirely of muscle-precursor tissue. In this way we have implicated hundreds of “new” genes in muscle and neural development.

Hox genes are fascinating genes that control where parts of the body form. For example, mutations in these genes can lead to the growth of a leg in lieu of an antenna. Similar genes in all animals govern the placement of body parts along the head-to-tail axis. We are using a variety of approaches to identify target genes that lie directly or indirectly downstream of Hox proteins (transcription factors), which are a subset of the large group of homeodomain proteins. We have identified and studied target genes regulated by two other homeodomain proteins, Ventral nerve defective (Vnd) and Tinman (Tin). We used yeast genetic approaches to screen the fly genome for candidate target genes. In the case of Vnd, a new target gene we found provided striking evidence that the organization of the central nervous system along the dorsal-ventral axis has common features in flies and mice. For Tin, we have identified targets that play a role in development of the musculature, including a gene called jelly belly that encodes a new type of signaling protein.