Distinct gene expression profiles and reduced JNK signaling in retinitis pigmentosa caused by RP1 mutations.
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.
Liu
Jiewu
J
Department of Developmental Neurobiology, St Jude Children's Research Hospital, Memphis, TN 38105-2794, USA.
Huang
Qian
Q
Higdon
Jason
J
Liu
Wei
W
Xie
Tao
T
Yamashita
Tetsuji
T
Cheon
Kyeogmi
K
Cheng
Cheng
C
Zuo
Jian
J
D000818:Animals; D050976:Basic-Leucine Zipper Transcription Factors / Q000235:genetics; D054707:Cyclic Nucleotide Phosphodiesterases, Type 6; D015536:Down-Regulation; D005136:Eye Proteins / Q000235:genetics; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental; D018398:Homeodomain Proteins / Q000235:genetics; D048031:JNK Mitogen-Activated Protein Kinases / Q000032:analysis / Q000378:metabolism*; D051379:Mice; D008817:Mice, Mutant Strains; D008869:Microtubule-Associated Proteins / Q000032:analysis / Q000235:genetics*; D009154:Mutation; D020411:Oligonucleotide Array Sequence Analysis; D010727:Phosphoric Diester Hydrolases / Q000235:genetics; D012174:Retinitis Pigmentosa / Q000201:enzymology* / Q000235:genetics* / Q000628:therapy; D012374:Rod Cell Outer Segment / Q000737:chemistry; D015398:Signal Transduction; D015534:Trans-Activators / Q000235:genetics
D050976:Basic-Leucine Zipper Transcription Factors; D005136:Eye Proteins; D018398:Homeodomain Proteins; D008869:Microtubule-Associated Proteins; C084884:Nrl protein, mouse; C497821:RP1 protein, mouse; D015534:Trans-Activators; C109288:cone rod homeobox protein; D048031:JNK Mitogen-Activated Protein Kinases; D010727:Phosphoric Diester Hydrolases; D054707:Cyclic Nucleotide Phosphodiesterases, Type 6; C517438:Pde6b protein, mouse