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Zhang Y Goss AM Cohen ED Kadzik R Lepore JJ Muthukumaraswamy K Yang J DeMayo FJ Whitsett JA Parmacek MS Morrisey EE 《Nature genetics》2008,40(7):862-870
Epithelial organs, including the lung, are known to possess regenerative abilities through activation of endogenous stem cell populations, but the molecular pathways regulating stem cell expansion and regeneration are not well understood. Here we show that Gata6 regulates the temporal appearance and number of bronchioalveolar stem cells (BASCs) in the lung, its absence in Gata6-null lung epithelium leading to the precocious appearance of BASCs and concurrent loss in epithelial differentiation. This expansion of BASCs was the result of a pronounced increase in canonical Wnt signaling in lung epithelium upon loss of Gata6. Expression of the noncanonical Wnt receptor Fzd2 was downregulated in Gata6 mutants and increased Fzd2 or decreased beta-catenin expression rescued, in part, the lung epithelial defects in Gata6 mutants. During lung epithelial regeneration, canonical Wnt signaling was activated in the niche containing BASCs and forced activation of Wnt signaling led to a large increase in BASC numbers. Moreover, Gata6 was required for proper lung epithelial regeneration, and postnatal loss of Gata6 led to increased BASC expansion and decreased differentiation. Together, these data demonstrate that Gata6-regulated Wnt signaling controls the balance between progenitor expansion and epithelial differentiation required for both lung development and regeneration. 相似文献
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Lee K Jeong J Kwak I Yu CT Lanske B Soegiarto DW Toftgard R Tsai MJ Tsai S Lydon JP DeMayo FJ 《Nature genetics》2006,38(10):1204-1209
The hedgehog family of morphogens are regulators of cell proliferation, differentiation and cell-cell communication. These morphogens have been shown to have important roles in organogenesis, spermatogenesis, stem cell maintenance and oncogenesis. Indian hedgehog (encoded by Ihh) has been shown to be expressed in the uterine epithelium under the control of the steroid hormone, progesterone. Although in vivo and in vitro studies have shown that progesterone achieves its effects on uterine function through epithelial-stromal cross-talk, molecular mediator(s) for this cellular communication pathway have not been elucidated. Using new experimental approaches that ablate Ihh specifically in Pgr-positive uterine cells of the mouse, we demonstrate that Ihh is an essential mediator of Pgr action in the uterus, and expression of this factor is critical in mediating the communication between the uterine epithelium and stroma required for embryo implantation. 相似文献
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Arteries and veins are anatomically, functionally and molecularly distinct. The current model of arterial-venous identity proposes that binding of vascular endothelial growth factor to its heterodimeric receptor--Flk1 and neuropilin 1 (NP-1; also called Nrp1)--activates the Notch signalling pathway in the endothelium, causing induction of ephrin B2 expression and suppression of ephrin receptor B4 expression to establish arterial identity. Little is known about vein identity except that it involves ephrin receptor B4 expression, because Notch signalling is not activated in veins; an unresolved question is how vein identity is regulated. Here, we show that COUP-TFII (also known as Nr2f2), a member of the orphan nuclear receptor superfamily, is specifically expressed in venous but not arterial endothelium. Ablation of COUP-TFII in endothelial cells enables veins to acquire arterial characteristics, including the expression of arterial markers NP-1 and Notch signalling molecules, and the generation of haematopoietic cell clusters. Furthermore, ectopic expression of COUP-TFII in endothelial cells results in the fusion of veins and arteries in transgenic mouse embryos. Thus, COUP-TFII has a critical role in repressing Notch signalling to maintain vein identity, which suggests that vein identity is under genetic control and is not derived by a default pathway. 相似文献
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