Expression of brain‐specific angiogenesis inhibitor 3 (BAI3) in normal brain and implications for BAI3 in ischemia‐induced brain angiogenesis and malignant glioma

Abstract

Murine brain-specific angiogenesis inhibitor 1 and 2 (mBAI1, mBAI2) are involved in angiogenesis after cerebral ischemia. In this study, mBAI3 was cloned and characterized. Northern and Western blot analyses demonstrated a unique developmental expression pattern in the brain. The level of mBAI3 in brain peaked 1 day after birth, unlike mBAI1 and mBAI2, which peaked 10 days after birth. In situ hybridization analyses of the brain showed the same localization of BAI3 as BAI1 and BAI2, which includes most neurons of cerebral cortex and hippocampus. In the in vivo focal cerebral ischemia model, BAI3 expression decreased from 0.5 h after hypoxia until 8 h, but returned to control level after 24 h. The expression of vascular endothelial growth factor following ischemia showed an inverse pattern. The decreased expressions of BAIs in high-grade gliomas were observed, but BAI3 expression was generally lower in malignant gliomas than in normal brain. Our results indicate that the expression and distribution of BAI3 in normal brain, but not its developmental expression, are very similar to those of BAI1 and BAI2, and that BAI3 may participate in the early phases of ischemia-induced brain angiogenesis and in brain tumor progression.

The cell-adhesion G protein-coupled receptor BAI3 is a high-affinity receptor for C1q-like proteins

“…Furthermore, although the BAI3 fragment binding to C1ql3 blocked the effect of C1ql3 on synapse density, it is possible that C1ql3 decreases synapse density by binding to a protein other than BAI3 on the neuronal surface. Nonetheless, the high affinity and specificity of C1ql protein binding to BAI3, along with the strong expression of BAI3 in pyramidal hippocampal neurons (15), strongly support the notion that their interaction underlies the effect of C1ql proteins on synapse density. Finally, some basic questions-such as that of the localization of BAI3-also remain to be addressed.…”

“…In mice, the largely brain-specific expression of BAI3 peaks during neonatal development but persists throughout adult life at lower levels (15). Interestingly, two SNPs within the human BAI3 gene have been significantly associated with schizophrenia in genome-wide association studies (28).…”

“…The antiangiogenic activity of BAI1 is thought to be mediated by a fragment of its N-terminal extracellular sequence, a fragment known as vasculostatin (17,23,24). BAI2 and BAI3 expression are not p53-inducible, but both proteins also act as inhibitors of angiogenesis (11,14,15,25). Moreover, BAI1 functions as a surface receptor for phosphatidylserine that is exposed on the surface of apoptotic cells, suggesting that BAI1 is an engulfment receptor that can initiate phagocytosis (26).…”

“…The extracellular sequences of BAI proteins are composed of an N-terminal CUB domain, five (BAI1) or four (BAI2 and BAI3) thrombospondin type 1 repeats, a hormonebinding domain, and the GPS (10,11). RNA quantification and in situ hybridization have indicated that in adult mice, BAI proteins are expressed primarily in the brain, with low-level expression in other tissues (12)(13)(14)(15). The BAI1 gene, originally identified in a screen for p53-inducible genes, is thought to inhibit neovascularization, a process required for tumor growth (10,13,(16)(17)(18)(19).…”

C1q/Tumor Necrosis Factor-related Protein 11 (CTRP11), a Novel Adipose Stroma-derived Regulator of Adipogenesis

“…It is unclear whether the GST fusion protein made in bacteria is properly assembled into its native higher-order oligomeric structures, likely to be functionally relevant. Importantly, the expression of BAI3 is highly restricted to the brain (64,65), in striking contrast to the expression of CTRP11 by a variety of tissues in addition to the central nervous system. Although published studies (64,65) and the available database in NCBI indicate that BAI3 is not expressed in human and mouse adipose tissue, it still remains to be determined whether pre-adipocytes express BAI3 and whether it mediates the suppressive effect of CTRP11 on adipocyte differentiation.…”