Retinal degeneration following failed photoreceptor maturation in 5A11/basigin null mice.

5A11/Basigin is a member of the immunoglobulin gene superfamily which plays an important role in cell-cell interactions in the developing neural retina. These studies were initiated to investigate the distribution of 5A11/Basigin within the mouse retina, as well as the cytoarchitectural and biochemical effects on the retina after the inactivation of the 5A11/Basigin gene in a mouse strain. Immunocytochemical analyses indicated that mouse 5A11/Basigin is located on the surface of Müller cells, the apical and basal surfaces of the retinal pigmented epithelium, and blood vessels. Lower expression levels were found on photoreceptor cell bodies and a portion of the inner segments. Inactivation of the 5A11/Basigin gene in mice resulted in the failure of photoreceptor cells to fully mature. This failed development eventually lead to the degeneration, death and removal of most of the photoreceptors several months after birth. Biochemical analyses indicated that expression of Müller cell specific proteins, including glutamine synthetase and carbonic anhydrase-II, was not effected; however, opsin protein expression never achieved normal adult levels in the 5A11/Basigin null mice. Also, 5A11/Basigin null retinas were considered 'reactive' based on elevated glial fibrillary acidic protein expression. The results presented here suggest that 5A11/Basigin expression on Müller cells and/or the retinal pigmented epithelium is necessary for photoreceptor outer segment biochemical development and structural maintenance. However, the exact role that 5A11/Basigin plays during retinal development remains to be determined.

Role of STAT3 and C/EBP in cytokine-dependent expression of the mouse serum amyloid P-component (SAP) and C-reactive protein (CRP) genes.

Inflammation is accompanied by a rapid increase in blood levels of acute phase proteins synthesized by hepatocytes in response to cytokines. Although C-reactive protein (CRP) levels increase dramatically in most mammals, the major acute phase protein in the mouse is the homologous pentraxin, serum amyloid P-component (SAP), whereas CRP is a minor acute phase reactant. The molecular basis for the pronounced difference in SAP and CRP gene expression in the mouse is unknown. Transfection of ++/Li mouse hepatoma cells with CAT-reporter constructs containing the 5'-flanking region of the mouse CRP gene indicated that transcription was stimulated by either IL-6, or IL-6 plus IL-1, when > or =360 bp of the 5'-proximal DNA was present. Examination of the 5'-flanking region of the mouse SAP gene revealed that the region between -433 and -397 from the transcription start site responded to IL-1 and IL-6 by binding both STAT3 and C/EBPbeta. This responsive region consisted of two adjacent C/EBPbeta consensus sites that overlap with two STAT3 consensus sites and was found to bind C/EBPbeta at an upstream site of -427 to -409 and STAT3 at a downstream site of -415 to -397. By contrast, the 360 bp promoter of the CRP gene was bound only by STAT3 at consensus sites at -93, -142, -173, and -287 from the start site; however, a single consensus site for C/EBP at -75 was not recognized. STAT3 appears to be necessary for both mouse SAP and CRP gene transcription since overexpression of an inactive, deletion mutant of STAT3 inhibited transcription of both genes. The results indicate that both STAT3 and C/EBPbeta participate in mouse SAP gene expression, whereas only STAT3 is involved in mouse CRP gene expression. The findings for mouse SAP gene expression are consistent with the reported interaction between these two transcription factors for human CRP gene transcription.