David Rowitch, M.D., Ph.D.

Associate Professor of Pediatrics

Research in my laboratory is largely focused on divergent roles for Hedgehog signaling during CNS development and in disease.

1. Cell cycle regulation in CNS development and tumorigenesis by Sonic hedgehog.
Molecular insight into the etiology of human CNS malformations and cancer has emerged from investigation of the genetic pathways that underlay normal brain development. The Hedgehog pathway is implicated in the etiology of the pediatric cerebellar tumor, medulloblastoma, and is essential for proliferation of cerebellar precursors during development. Our work indicates that Shh has direct mitogenic effects on cerebellar precursor cells and rapidly causes upregulation of D- and E-type cyclins via function of the proto-oncogene N-myc.
2. Neural specification by Sonic hedgehog: Olig gene regulation and function.
In collaboration with Chuck Stiles laboratory, we have characterized the Shh-regulated Olig1 and Olig2 genes, essential for development of oligodendrocytes throughout the CNS. In addition, Olig gene function is also required for development of motor neurons of the spinal cord. This dual requirement for Olig function and other lines of evidence call into question the traditional view that oligodendrocytes develop via a glial-restricted precursor cell. In a collaborative effort, we have further shown that human OLIG gene expression serves as a marker to for human gliomas. Our work also seeks to better understand the process of glial specification.
3. Large scale screen for regulators of gliogenesis.

Ongoing work in the lab seeks to better understand the genetics of oligodendrocyte and astrocyte development via identification of novel factors expressed glial precursors in vivo.

References:

• T.Sun, Y.Echelard, R.Lu, D. Yuk, S.Kaing, C.D.Stiles and D.H.Rowitch (2001). Olig basic helix-loop-helix proteins interact with homeodomain proteins to regulate cell fate acquisition in progenitors of the ventral neural tube. Curr. Biol. 18, 1413-1420.
• Q. R. Lu, T. Sun, Z. Zhu, N. Ma, M. Garcia, C. D. Stiles and D. H. Rowitch (2002). Common developmental requirement for Olig function indicates a motor neuron/oligodendrocyte lineage connection. Cell 109, 75-86.
• Q. Zhao, A. Kho, A.M. Kenney, D. Yuk, I. Kohane and D.H. Rowitch (2002). Identification of genes expressed with temporal-spatial restriction to developing cerebellar neuron precursors by a functional genomic approach. PNAS, 99, 5704-5709.
• A.M. Kenney, M.D. Cole and D.H. Rowitch (2003). N-myc upregulation by Sonic hedgehog signaling promotes proliferation in developing cerebellar granule neuron precursors. Development 130, 15-28.
• K.L. Ligon, Y. Echelard, S. Tole, P. Danielian, S. Kiang, E. Grove, A.P.McMahon and D.H.Rowitch (2003). Loss of Emx2 function leads to ectopic