Matthew Scott

Research/Lab website:   Scott Lab Home Page

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. Transcription factors necessary for forming particular parts of the body—such as head-to-tail differences, heart, 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. We study evolutionarily conserved regulators in flies and in mice to learn how the embryo is constructed and how pattern-organizing genetic programs arose, function, and change. Genetic damage to developmental regulators can lead to cancer, birth defects, and neurodegeneration; we study all of these processes in the mammalian cerebellum.

The Hedgehog Signaling System in Development and Cancer

The Hedgehog (Hh) signaling system is used in most animals to control the embryonic development of numerous tissues, such as brain and spinal cord, limbs, skeleton, and skin. We have asked three questions about Hh signaling: (1) Where does the signal go from and to? (2) What information does it carry? (3) How is the signal received, transduced, and interpreted? Mutations in human PATCHED (PTCH) cause birth defects and medulloblastoma of the cerebellum, the most common childhood malignant brain tumor, and basal cell carcinoma of the skin, the most common human cancer. We are using mutant ptc mouse models to investigate how normal cerebellum cells become tumor cells. We are studying detailed mechanisms of Hh signal transduction including sterol effects. We are also investigating genetic control of normal cerebellum development in mice and zebrafish.

Molecular of the Niemann-Pick type C syndrome, a neurodegenerative disorder

Children mutant in either of the two NPC genes undergo neurodegeneration and usually die by the teenage years. Mutant cells accumulate masses of sterols in aberrant organelles due to defective intracellular trafficking. In humans and mice, NPC disease causes the death of the Purkinje neurons of the cerebellum. We are now studying what the NPC proteins do within Purkinje neurons. Flies have npc1 and npc2 genes. We made mutants in both and found defects highly similar to those seen in mutant npc mammalian cells. Fly npc is required to produce the steroid molting hormone, ecdysone. We continue to investigate Npc genes in mice and flies to determine the exact functions of the proteins.

Rab proteins in development and cell biology

Small proteins called Rabs are used to control movements of organelles and assembly of subcellular compartments and skeletal elements. For 31 fly Rab genes, we made versions that are uncontrollably active, normal, or that will interfere with the function of the normal gene. By activating production of a Rab protein at specific times and places, we are investigating the functions of each Rab in cell biology and development.

Chromatin factors in embryonic stem cells

By monitoring gene expression in carefully staged embryos we were able to discover changes in pattern of transcription during key events in mouse and fly embryonic pattern formation. Massive changes occur in transcription in very early mouse embryos, as the embryo develops from a single cell into 32 cells. We have begun to investigate the roles of chromatin proteins in pre-implantation mouse embryos and in cultured mouse embryonic stem cells.

Vertebrate functions of Planar Cell Polarity (PCP) genes

PCP proteins form a signaling system that coordinates the polarity of cells within epithelial sheets. With Prof. Jeff Axelrod in the Department of Pathology at Stanford, we are examining roles of vertebrate planar cell polarity (PCP) genes in inner ear hair cells and in brain development.