Breast carcinoma-amplified sequence 2 regulates adult neurogenesis via β-catenin

Background: Breast carcinoma-amplified sequence 2 (BCAS2) regulates beta-catenin gene splicing. The conditional knockout of BCAS2 expression in the forebrain (BCAS2 cKO) of mice confers impaired learning and memory along with decreased beta-catenin expression. Because beta-catenin reportedly regulates adult neurogenesis, we wondered whether BCAS2 could regulate adult neurogenesis via beta-catenin. Methods: BCAS2-regulating neurogenesis was investigated by characterizing BCAS2 cKO mice. Also, lentivirus-shBCAS2 was intracranially injected into the hippocampus of wild-type mice to knock down BCAS2 expression. We evaluated the rescue effects of BCAS2 cKO by intracranial injection of adeno-associated virus encoding BCAS2 (AAV-DJ8-BCAS2) and AAV-beta-catenin gene therapy. Results: To show that BCAS2-regulating adult neurogenesis via beta-catenin, first, BCAS2 cKO mice showed low SRY-box 2-positive (Sox2(+)) neural stem cell proliferation and doublecortin-positive (DCX+) immature neurons. Second, stereotaxic intracranial injection of lentivirus-shBCAS2 knocked down BCAS2 in the hippocampus of wild-type mice, and we confirmed the BCAS2 regulation of adult neurogenesis via beta-catenin. Third, AAV-DJ8-BCAS2 gene therapy in BCAS2 cKO mice reversed the low proliferation of Sox2(+) neural stem cells and the decreased number of DCX+ immature neurons with increased beta-catenin expression. Moreover, AAV-beta-catenin gene therapy restored neuron stem cell proliferation and immature neuron differentiation, which further supports BCAS2-regulating adult neurogenesis via beta-catenin. In addition, cells targeted by AAV-DJ8 injection into the hippocampus included Sox2 and DCX immature neurons, interneurons, and astrocytes. BCAS2 may regulate adult neurogenesis by targeting Sox2(+) and DCX+ immature neurons for autocrine effects and interneurons or astrocytes for paracrine effects. Conclusions: BCAS2 can regulate adult neurogenesis in mice via beta-catenin.

Automated summary

This study found that BCAS2 can regulate adult neurogenesis in mice by modulating beta-catenin. BCAS2 cKO mice showed decreased proliferation of neural stem cells and immature neurons. Gene therapy was able to reverse these changes and increase beta-catenin expression.