Characterization of the proneural gene regulatory network during mouse telencephalon development.
BACKGROUND
The proneural proteins Mash1 and Ngn2 are key cell autonomous regulators of neurogenesis in the mammalian central nervous system, yet little is known about the molecular pathways regulated by these transcription factors.


RESULTS
Here we identify the downstream effectors of proneural genes in the telencephalon using a genomic approach to analyze the transcriptome of mice that are either lacking or overexpressing proneural genes. Novel targets of Ngn2 and/or Mash1 were identified, such as members of the Notch and Wnt pathways, and proteins involved in adhesion and signal transduction. Next, we searched the non-coding sequence surrounding the predicted proneural downstream effector genes for evolutionarily conserved transcription factor binding sites associated with newly defined consensus binding sites for Ngn2 and Mash1. This allowed us to identify potential novel co-factors and co-regulators for proneural proteins, including Creb, Tcf/Lef, Pou-domain containing transcription factors, Sox9, and Mef2a. Finally, a gene regulatory network was delineated using a novel Bayesian-based algorithm that can incorporate information from diverse datasets.


CONCLUSIONS
Together, these data shed light on the molecular pathways regulated by proneural genes and demonstrate that the integration of experimentation with bioinformatics can guide both hypothesis testing and hypothesis generation.
Gohlke
Julia M
JM
Environmental Systems Biology Group, Laboratory of Molecular Toxicology, National Institute of Environmental Health Sciences, RTP, NC 27709, USA. gohlkej@niehs.nih.gov
Armant
Olivier
O
Parham
Frederick M
FM
Smith
Marjolein V
MV
Zimmer
Celine
C
Castro
Diogo S
DS
Nguyen
Laurent
L
Parker
Joel S
JS
Gradwohl
Gerard
G
Portier
Christopher J
CJ
Guillemot
François
F
D000465:Algorithms; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics*; D001499:Bayes Theorem; D002448:Cell Adhesion / Q000235:genetics; D019295:Computational Biology; D004622:Embryo, Mammalian; D018507:Gene Expression Regulation, Developmental; D053263:Gene Regulatory Networks; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics*; D009474:Neurons / Q000166:cytology*; D015398:Signal Transduction / Q000235:genetics; D013687:Telencephalon / Q000196:embryology*
D051792:Basic Helix-Loop-Helix Proteins; D009419:Nerve Tissue Proteins; C499317:Ascl1 protein, mouse; C102938:Neurog2 protein, mouse