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Human Molecular Genetics Advance Access originally published online on August 26, 2005
Human Molecular Genetics 2005 14(19):2945-2958; doi:10.1093/hmg/ddi325
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© The Author 2005. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Distinct gene expression profiles and reduced JNK signaling in retinitis pigmentosa caused by RP1 mutations

Jiewu Liu1, Qian Huang1, Jason Higdon1, Wei Liu2, Tao Xie3, Tetsuji Yamashita1, Kyeogmi Cheon1, Cheng Cheng2 and Jian Zuo1,*

1Department of Developmental Neurobiology, 2Department of Biostatistics and 3Hartwell Centre, St Jude Children's Research Hospital, Memphis, TN 38105-2794, USA

* To whom correspondence should be addressed. Tel: +1 9014953891; Fax: +1 9014952270; Email: jian.zuo{at}stjude.org

Received July 18, 2005; Accepted August 23, 2005

To understand the mechanisms underlying autosomal dominant progressive retinitis pigmentosa (RP) caused by the mutations of the RP1 gene and to identify molecules that play roles in the early disease process, we used Affymetrix U74Av2 microarrays to compare the gene expression profiles of retinas from Rp1–/– and Rp1+/+ mice at postnatal days (P) 7, 10, 14, 18 and 21. These profiles were independently verified by comparison with results of retinal serial analysis of gene expression, U74Av2 array studies of mouse retinas, real-time PCR and in situ hybridization. We found that the disruption of Rp1 significantly affected the expression of multiple clusters of genes whose products were involved in diverse biological pathways. The molecular responses to the disruption of Rp1 changed dramatically during development and were distinct from responses to the disruption of photoreceptor transcription factors (Crx–/– or Nrl–/–) and a phototransduction molecule (Pde6brd1). We found specific alterations of gene expression in the c-Jun N-terminal kinase (JNK) signaling cascades. Western analysis confirmed that the phosphorylation of key members in the JNK signaling cascades (i.e. JNK1, JNK2, MAP2, MKK4 and c-Jun) is reduced, whereas phospho-ERK and phospho-p38 are unchanged, in Rp1–/– retinas at P18–21. Immunostaining demonstrated that, like Rp1, phospho-JNKs and phospho-MAP2 are present in outer segments of photoreceptors. Our studies reveal unique molecular phenotypes in multiple biological pathways and the specific reduction of JNK signaling cascades in RP1 diseases, and suggest that RP1, a doublecortin-containing microtubule associated protein, and JNK signaling cascades play integral roles in photoreceptor development and maintenance. Our studies further suggest JNK-related therapeutic strategies for RP1 diseases.


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