Disruption of PAX6 function in mice homozygous for the Pax6(Sey-1Neu) mutation produces abnormalities in the early development and regionalization of the diencephalon
MECHANISMS OF DEVELOPMENT
Authors: Grindley, JC; Hargett, LK; Hill, RE; Ross, A; Hogan, BLM
Abstract
Pax6 expression in the diencephalon of the mouse embryo is restricted both antero-posteriorly and dorso-ventrally, with changes in level occurring at prosomere boundaries. Small eye (Pax6(Sey-1Neu)) mice homozygous for Pax6 mutations have multiple defects in early forebrain development. In the diencephalon of Pax6(Sey-1Neu)/Pax6(Sey-1Neu) mice there is an apparent enlargement of the zona limitans (the boundary region between prosomeres p2 and p3), and a blurring of the p1-p2 boundary. PAX6 function is also required for the normal development of the posterior commissure at the midbrain-pi boundary. In the posterior diencephalon PAX6 appears to regulate its own transcription, and that of Wnt7b. In p2 and p3, ventral markers are expressed more dorsally than normal, and this is accompanied in p3 by a reduction in the size of the zona incerta. Thus, PAX6 is essential for the normal development and regionalization of the diencephalon. (C) 1997 Elsevier Science Ireland Ltd.
Lung cancer deficient in the tumor suppressor GATA4 is sensitive to TGFBR1 inhibition
NATURE COMMUNICATIONS
Authors: Gao, Lei; Hu, Yong; Tian, Yahui; Fan, Zhenzhen; Wang, Kun; Li, Hongdan; Zhou, Qian; Zeng, Guandi; Hu, Xin; Yu, Lei; Zhou, Shiyu; Tong, Xinyuan; Huang, Hsinyi; Chen, Haiquan; Liu, Qingsong; Liu, Wanting; Zhang, Gong; Zeng, Musheng; Zhou, Guangbiao; He, Qingyu; Ji, Hongbin; Chen, Liang
Abstract
Lung cancer is the leading cause of cancer-related deaths worldwide. Tumor suppressor genes remain to be systemically identified for lung cancer. Through the genome-wide screening of tumor-suppressive transcription factors, we demonstrate here that GATA4 functions as an essential tumor suppressor in lung cancer in vitro and in vivo. Ectopic GATA4 expression results in lung cancer cell senescence. Mechanistically, GATA4 upregulates multiple miRNAs targeting TGFB2 mRNA and causes ensuing WNT7B downregulation and eventually triggers cell senescence. Decreased GATA4 level in clinical specimens negatively correlates with WNT7B or TGF-beta 2 level and is significantly associated with poor prognosis. TGFBR1 inhibitors show synergy with existing therapeutics in treating GATA4-deficient lung cancers in genetically engineered mouse model as well as patient-derived xenograft (PDX) mouse models. Collectively, our work demonstrates that GATA4 functions as a tumor suppressor in lung cancer and targeting the TGF-beta signaling provides a potential way for the treatment of GATA4-deficient lung cancer.
COA
Certificate of Analysis
