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Human Molecular Genetics Advance Access published online on August 26, 2005
Human Molecular Genetics, doi:10.1093/hmg/ddi325
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© The Author 2005. Published by Oxford University Press. All rights reserved
Received July 18, 2005
Revised August 23, 2005
Accepted August 23, 2005

Article

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

Jiewu Liu 1, Qian Huang 1, Jason Higdon 1, Wei Liu 2, Tao Xie 3, Tetsuji Yamashita 1, Kyeogmi Cheon 1, Cheng Cheng 2, and Jian Zuo 4*

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

* To whom correspondence should be addressed.
Jian Zuo, E-mail: jian.zuo{at}stjude.org


  Abstract

To understand the mechanisms underlying autosomal dominant progressive retinitis pigmentosa (RP) caused by 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 (SAGE), U74Av2 array studies of mouse retinas, real-time PCR and in situ hybridization. We found that 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 those 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 is 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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