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ACS Chem Neurosci 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 Chem Neurosci
Date Published2010 Jan 28

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.


Alternate JournalACS Chem Neurosci
PubMed ID20495671
PubMed Central IDPMC2873204
Grant ListR21 MH087896 / MH / NIMH NIH HHS / United States
R21 MH076146 / MH / NIMH NIH HHS / United States
R33 MH087896 / MH / NIMH NIH HHS / United States
R21 MH076146-01 / MH / NIMH NIH HHS / United States
R21 MH076146-02 / MH / NIMH NIH HHS / United States
N01CO12400 / CA / NCI NIH HHS / United States
R21 MH087896-01 / MH / NIMH NIH HHS / United States