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ACS chemical neuroscience DOI:10.1021/cn900046a

Chemical genetics identifies small-molecule modulators of neuritogenesis involving neuregulin-1/ErbB4 signaling.

Publication TypeJournal Article
Year of Publication2010
AuthorsKuai, L, Wang, X, Madison, JM, Schreiber, SL, Scolnick, EM, Haggarty, SJ
JournalACS chemical neuroscience
Volume1
Issue4
Pages325-342
Date Published2010/01/28
Abstract

Genetic findings have suggested that neuregulin-1 (Nrg1) and its receptor v-erb-a erythroblastic leukemia viral oncogene homolog 4 (ErbB4) may play a role in neuropsychiatric diseases. However, the downstream signaling events and relevant phenotypic consequences of altered Nrg1 signaling in the nervous system remain poorly understood. To identify small molecules for probing Nrg1-ErbB4 signaling, a PC12-cell model was developed and used to perform a live-cell, image-based screen of the effects of small molecules on Nrg1-induced neuritogenesis. By comparing the resulting phenotypic data to that of a similar screening performed with nerve growth factor (NGF), this multidimensional screen identified compounds that directly inhibit Nrg1-ErbB4 signaling, such as the 4-anilino-quinazoline Iressa (gefitinib), as well as compounds that potentiate Nrg1-ErbB4 signaling, such as the indolocarbazole K-252a. These findings provide new insights into the regulation of Nrg1-ErbB4 signaling events and demonstrate the feasibility of using such a multidimensional, chemical-genetic approach for discovering probes of pathways implicated in neuropsychiatric diseases.

DOI10.1021/cn900046a
Pubmed

http://www.ncbi.nlm.nih.gov/pubmed/20495671?dopt=Abstract