Contact Information:

Dana-Farber Cancer Institute

Division of Cellular and
Molecular Biology

Smith Research Building,
Room 1070

44 Binney Street

Boston, MA 02115

phone: 617-632-3512

fax: 617-632-4663

charles_stiles@dfci.harvard.edu

Research Summary

Neurons, oligodendrocytes and astrocytes in the developing mammalian cortex are thought to arise from a common, multipotent progenitor cell. In cell culture, the fate choices of this progenitor can be regulated by growth factors and organizing signals such as Sonic hedgehog (Shh). For example, platelet-derived growth factor (PDGF) "instructs" towards a neuronal phenotype. Ciliary neurotrophic factor (CNTF) induces formation of astrocytes and Shh promotes formation of early oligodendrocytes. The broad goal of the Stiles laboratory is to define the intracellular mediators of these extracellular developmental cues.

Adenovirus expression vectors are used to define signal transduction pathways that promote formation of neurons in response to PDGF. Downstream genetic targets of PDGF and CNTF are being captured and characterized in a large-scale "undirected" genetic screen. These factor-responsive cDNA clones can be arrayed on glass "chips" to profile the genetic responses to PDGF and CNTF that result in different developmental outcomes. A "directed" genetic screen has been used recently to isolate a pair of Shh-responsive transcription factors that promote the formation of oligodendrocytes. In collaboration with faculty colleague David Rowitch, we are constructing mutant mouse strains bearing targeted disruptions of these transcription factors.

Selected Publications

Lu QR, Cai L, Rowitch D, Cepko CL, Stiles CD. Ectopic expression of Olig1 promotes oligodendrocyte formation and reduces neuronal survival in developing mouse cortex. Nat Neurosci. 2001 Oct;4(10):973-4.

Sun T, Echelard Y, Lu R, Yuk DI, Kaing S, Stiles CD, Rowitch DH. Olig bHLH proteins interact with homeodomain proteins to regulate cell fate acquisition in progenitors of the ventral neural tube. Curr Biol. 2001 Sep 18;11(18):1413-20.

Lu QR, Park JK, Noll E, Chan JA, Alberta J, Yuk D, Alzamora MG, Louis DN, Stiles CD, Rowitch DH, Black PM. Oligodendrocyte lineage genes (OLIG) as molecular markers for human glial brain tumors. Proc Natl Acad Sci U S A. 2001 Sep 11;98(19):10851-6.

Kim HA, Ratner N, Roberts TM, Stiles CD. Schwann cell proliferative responses to cAMP and Nf1 are mediated by cyclin D1. J Neurosci. 2001 Feb 15;21(4):1110-6.

Kilic T, Alberta JA, Zdunek PR, Acar M, Iannarelli P, O'Reilly T, Buchdunger E, Black PM, Stiles CD. Intracranial inhibition of platelet-derived growth factor-mediated glioblastoma cell growth by an orally active kinase inhibitor of the 2-phenylaminopyrimidine class. Cancer Res. 2000 Sep 15;60(18):5143-50.