Charles D. Stiles, PhD
Professor of Microbiology and
Molecular Genetics
Harvard Medical School/Dana-Farber
Cancer Center
MRRC Project(s)
P01 HD24926-11
Signal Transduction in Embryo Development- Program Director and PI,
Prj 1: Immediate Early Genes in Neural Fate Choice
Neurons, oligodendrocytes and astrocytes in the developing mammalian cortex
are thought to arise from smaller subsets of pluripotent progenitor cells.
In culture, the fate choices of these progenitor cells can be regulated
by growth factors and organizing signals such as Sonic hedgehog (Shh).
For example, cortical progenitor cells from E14 rat embryos are "instructed"
by platelet-derived growth factor (PDGF) 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 transcription factors that mediate the
cellular response to these extracellular developmental cues. We are particularly
interested in transcription factors that instruct formation of the two
principle types of macroglia in the brain - oligodendrocytes and astrocytes.
Research Description
Major Results
In a "directed screen" for basic helix-loop-helix (bHLH) transcription
factors that instruct towards the glial lineages, we isolated a pair of
novel new bHLH transcription factors that we have termed "OLIG1" and "OLIG2".
With collaborator David Rowitch, a neonatologist at Children's Hospital,
we have shown that OLIG1 and OLIG2 direct formation of two clinically
relevant neural cell types - motor neurons and oligodendrocytes. The two
OLIG genes map to a region of chromosome 21 associated with severe mental
retardation in Down patients. There are less that 50 known or predicted
genes within this region and OLIG1/2 are the only bHLH genes within this
domain. It is therefore of interest that sustained misexpression of OLIG1
in developing mouse brain causes postnatal neuronal cell death. Down syndrome
has multiple phenotypic traits. However, a universal feature of the Down
syndrome phenotype is mental retardation resulting, in part, from age-related
neuronal degeneration.
In a collaborative "undirected screen" we are creating a genome-wide atlas
of transcription factor expression in the developing brain. Together with
the laboratories of David Rowitch and Qiufu Ma (Children's Hospital and
Dana-Farber Cancer Institute) we have compiled a near comprehensive list
of the transcription factors that are encoded in the human genome (~1,400
in total). We have isolated the murine orthologs of these human genes
as cDNA clones. Using the method of in situ hybridization, we visualize
the expression of these transcription factors in developing mouse embryos.
The in situ images are scanned into a computerized database that will
be accessible to the scientific community via the world wide web. It is
our hope that a manageable subset of this vertebrate "transcriptome" will
be expressed at spatially restricted positions in developing brain. Spatially
restricted transcription factors will shed light on formation of specific
neural subtypes as well as formation of astrocytes - the other principle
type of vertebrate macroglia.
Publications
Segal RA, Bhattacharyya A, Rua LA, Alberta JA, Stephens RM, Kaplan DR, Stiles CD. Differential utilization of Trk autophosphorylation sites. J Biol Chem 1996; 271:20175-81.
Williams BP, Park JK, Alberta JA, Muhlebach SG, Hwang GY, Roberts TM, Stiles CD. A PDGF-regulated immediate early gene response initiates neuronal differentiation in ventricular zone progenitor cells. Neuron 1997; 18:553-562.
Alberta JA, Stiles CD. Phosphorylation-directed antibodies in high-flux screens for compounds that modulate signal transduction. Biotechniques 1997; 23:490-493.
Kwon Y, Bhattacharyya A, Alberta J, Cheon K, Stiles C, Pomeroy S. Activation of p185erbB2 during Wallerian degeneration of sciatic nerve. J Neurosci 1997; 17:8293-8299.
Lu QR, Yuk D, Alberta JA, Zhu Z, Pawlitsky I, Chan J, McMahon AP, Stiles CD, Rowitch DR. Sonic hedgehog-regulated oligodendrocyte lineage genes encoding bHLH proteins in the mammalian central nervous system. Neuron 2000; 25:317-329.
Kim HA, Pomeroy SL,
Whoriskey W, Pawlitsky I, Benowitz LI, Sicinski P, Stiles CD, Roberts
TM. A developmentally regulated switch directs regenerative growth of
Schwann cells through cyclin D1. Neuron 2000;26:405-416.
Kilic T, Alberta JA, Zdunek P, .R., Acar M, Iannarelli P, O'Reilly T,
Buchdunger E, Black PM, Stiles CD. Intracranial inhibition of PDGF-mediated
glioblastoma cell growth by an orally active kinase inhibitor of the 2-phenylaminopyrimidine
class. Cancer Res 2000;60:5143-5150.
Tekki-Kessaris N, Woodruff R, Hall AC, Gaffield W, Kimura S, Stiles CD,
Rowitch DH, Richardson WD. Hedgehog-dependent oligodendrocyte lineage
specification in the telencephalon. Development 2001;128:2545-2554.
Lu QR, Park J, Noll e, Chan JA, Alberta J, Yuk D, Garcia Alzamora M, Louis
DN, Stiles Cd, Rowitch dH, Black PM. Oligodendrocyte lineage genes (OLIG)
as as molecular markers for human glial brain tumors. PNAS 2001;98:10851-10856.
Lu QR, Cai L, Rowitch DH, Cepko CL, Stiles CW. Ectopic expression of Olig
1 promotes formation of oligodendrocytes and is deleterious to neuronal
survival in developing mouse cortex. Nat Neurosci 2001;10:973-974.
Alberta J, Park-S-K., Mora J, Yuk D, Pawlitzky I, Iannarelli P, Vartanian
T, Stiles CD, Rowitch DH. Sonic hedgehog signaling is required during
an early phase of oligodendrocyte development in the mammalian brain.
MCN 2001;18:434-444.
Sauvageot CM, Stiles CD. Molecular mechanisms controlling cortical gliogenesis.
Curr Opin Neurobiol 2002;12(3):244-9.
Lu QR, Sun T, Zhu Z, Ma N, Garcia M, Stiles CD, Rowitch DH. Common developmental
requirement for Olig function indicates a motor neuron/oligodendrocyte
connection. Cell 2002;109(1):75-86.
Sun T, Dong H, Wu L, Kane M, Rowitch DH, Stiles CD. Cross-repressive interaction
of the Olig2 and Nkx2.2 transcription factors in developing neural tube
associated with formation of a specific physical complex. J Neurosci 2003;
23(29):9547-56.
Ross SE, Greenberg ME, Stiles CD. Basic helix-loop-helix factors in cortical
development. Neuron 2003;39(1):13-25.
Stiles CD. Lost in space: misregulated positional cues create tripotent
neural progenitors in cell culture. Neuron 2003;40:447-449.
Ligon KL, Alberta JA, Kho AT, Weiss J, Kwaan MR, Nutt CL, Louis DN, Stiles
CD, Rowitch DH. The oligodendroglial lineage marker OLIG2 is universally
expressed in diffuse gliomas. J Neuropath Exp Neurol 2004, in press.
See Dr. Stiles' publications via PubMed
Contact Information
E-mail:
Charles D. Stiles, PhD
Professor of Microbiology and
Molecular Genetics
Harvard Medical School/Dana Farber
Cancer Center
