Lowery JW, Frump AL, Anderson L, DiCarlo GE, Jones MT, de Caestecker MP. ID family protein expression and regulation in hypoxic pulmonary hypertension. (2010) Am J Physiol Regul Integr Comp Physiol 299: R1463-77
Show Abstract · Added January 5, 2011Bone morphogenetic protein (BMP) signaling has been linked to the development of pulmonary hypertension (PH). Inhibitors of differentiation (ID) proteins (ID1-4) are a family of basic helix-loop-helix transcription factors that are downstream targets of the BMP signaling pathway, but the role that ID proteins play in the development of PH is unknown. To address this, we evaluated pulmonary expression of ID proteins in a mouse model of hypoxia-induced PH. There is selective induction of ID1 and ID3 expression in hypoxic pulmonary vascular smooth muscle cells (VSMCs) in vivo, and ID1 and ID3 expression are increased by hypoxia in cultured pulmonary VSMCs in a BMP-dependent fashion. ID4 protein is barely detectable in the mouse lung, and while ID2 is induced in hypoxic peripheral VSMCs in vivo, it is not increased by hypoxia or BMP signaling in cultured pulmonary VSMCs. In addition, the PH response to chronic hypoxia is indistinguishable between wild type and Id1 null mice. This is associated with a compensatory increase in ID3 but not ID2 expression in pulmonary VSMCs of Id1 null mice. These findings indicate that ID1 is dispensable for mounting a normal pulmonary vascular response to hypoxia, but suggest that ID3 may compensate for loss of ID1 expression in pulmonary VSMCs. Taken together, these findings indicate that ID1 and ID3 expression are regulated in a BMP-dependent fashion in hypoxic pulmonary VSMCs, and that ID1 and ID3 may play a cooperative role in regulating BMP-dependent VSMC responses to chronic hypoxia. | Citation | 20881097 (PMID)
10.1152/ajpregu.00866.2009 (DOI) |
Anderson L, Lowery JW, Frank DB, Novitskaya T, Jones M, Mortlock DP, Chandler RL, de Caestecker MP. Bmp2 and Bmp4 exert opposing effects in hypoxic pulmonary hypertension. (2010) Am J Physiol Regul Integr Comp Physiol 298: R833-42
Show Abstract · Added January 5, 2011The bone morphogenetic protein (BMP) type 2 receptor ligand, Bmp2, is upregulated in the peripheral pulmonary vasculature during hypoxia-induced pulmonary hypertension (PH). This contrasts with the expression of Bmp4, which is expressed in respiratory epithelia throughout the lung. Unlike heterozygous null Bmp4 mice (Bmp4(LacZ/+)), which are protected from the development of hypoxic PH, mice that are heterozygous null for Bmp2 (Bmp2(+/-)) develop more severe hypoxic PH than their wild-type littermates. This is associated with reduced endothelial nitric oxide synthase (eNOS) expression and activity in the pulmonary vasculature of hypoxic Bmp2(+/-) but not Bmp4(LacZ/+) mutant mice. Furthermore, exogenous BMP2 upregulates eNOS expression and activity in intrapulmonary artery and pulmonary endothelial cell preparations, indicating that eNOS is a target of Bmp2 signaling in the pulmonary vasculature. Together, these data demonstrate that Bmp2 and Bmp4 exert opposing roles in hypoxic PH and suggest that the protective effects of Bmp2 are mediated by increasing eNOS expression and activity in the hypoxic pulmonary vasculature. | Citation | 20042692 (PMID)
PMC2838658 (PMCID)
10.1152/ajpregu.00534.2009 (DOI) |
Sparrow DB, Boyle SC, Sams RS, Mazuruk B, Zhang L, Moeckel GW, Dunwoodie SL, de Caestecker MP. Placental insufficiency associated with loss of Cited1 causes renal medullary dysplasia. (2009) J Am Soc Nephrol 20: 777-86
Show Abstract · Added January 5, 2011A number of studies have shown that placental insufficiency affects embryonic patterning of the kidney and leads to a decreased number of functioning nephrons in adulthood; however, there is circumstantial evidence that placental insufficiency may also affect renal medullary growth, which could account for cases of unexplained renal medullary dysplasia and for abnormalities in renal function among infants who had experienced intrauterine growth retardation. We observed that mice with late gestational placental insufficiency associated with genetic loss of Cited1 expression in the placenta had renal medullary dysplasia. This was not caused by lower urinary tract obstruction or by defects in branching of the ureteric bud during early nephrogenesis but was associated with decreased tissue oxygenation and increased apoptosis in the expanding renal medulla. Loss of placental Cited1 was required for Cited1 mutants to develop renal dysplasia, and this was not dependent on alterations in embryonic Cited1 expression. Taken together, these findings suggest that renal medullary dysplasia in Cited1 mutant mice is a direct consequence of decreased tissue oxygenation resulting from placental insufficiency. | Citation | 19297558 (PMID)
PMC2663829 (PMCID)
10.1681/ASN.2008050547 (DOI) |
Boyle S, Misfeldt A, Chandler KJ, Deal KK, Southard-Smith EM, Mortlock DP, Baldwin HS, de Caestecker M. Fate mapping using Cited1-CreERT2 mice demonstrates that the cap mesenchyme contains self-renewing progenitor cells and gives rise exclusively to nephronic epithelia. (2008) Dev Biol 313: 234-45
Show Abstract · Added January 5, 2011Classic tissue recombination and in vitro lineage tracing studies suggest that condensed metanephric mesenchyme (MM) gives rise to nephronic epithelium of the adult kidney. However, these studies do not distinguish between cap mesenchyme and pre-tubular aggregates comprising the condensed MM, nor do they establish whether these cells have self-renewing capacity. To address these questions, we generated Cited1-CreER(T2) BAC transgenic mice, which express tamoxifen-regulated Cre recombinase exclusively in the cap mesenchyme. Fate mapping was performed by crossing these mice with the Rosa26R(LacZ) reporter line and evaluating the location and cellular characteristics of LacZ positive cells at different time points following tamoxifen injection. These studies confirmed expected results from previous in vitro analysis of MM cell fate, and provide in vivo evidence that the cap mesenchyme does not contribute to collecting duct epithelium in the adult. Furthermore, by exploiting the temporally regulated Cre recombinase, these studies show that nephronic epithelium arising at different stages of nephrogenesis has distinct spatial distribution in the adult kidney, and demonstrate for the first time that the cap mesenchyme includes a population of self-renewing epithelial progenitor cells. | Citation | 18061157 (PMID)
PMC2699557 (PMCID)
10.1016/j.ydbio.2007.10.014 (DOI) |
Frank DB, Lowery J, Anderson L, Brink M, Reese J, de Caestecker M. Increased susceptibility to hypoxic pulmonary hypertension in Bmpr2 mutant mice is associated with endothelial dysfunction in the pulmonary vasculature. (2008) Am J Physiol Lung Cell Mol Physiol 294: L98-109
Show Abstract · Added January 5, 2011Patients with familial pulmonary arterial hypertension inherit heterozygous mutations of the type 2 bone morphogenetic protein (BMP) receptor BMPR2. To explore the cellular mechanisms of this disease, we evaluated the pulmonary vascular responses to chronic hypoxia in mice carrying heterozygous hypomorphic Bmpr2 mutations (Bmpr2 delta Ex2/+). These mice develop more severe pulmonary hypertension after prolonged exposure to hypoxia without an associated increase in pulmonary vascular remodeling or proliferation compared with wild-type mice. This is associated with defective endothelial-dependent vasodilatation and enhanced vasoconstriction in isolated intrapulmonary artery preparations. In addition, there is a selective decrease in hypoxia-induced, BMP-dependent, endothelial nitric oxide synthase expression and Smad signaling in the intact lungs and in cultured pulmonary microvascular endothelial cells from Bmpr2 delta Ex2/+ mutant mice. These findings indicate that the pulmonary endothelium is a target of abnormal BMP signaling in Bmpr2 delta Ex2/+ mutant mice and suggest that endothelial dysfunction contributes to their increased susceptibility to hypoxic pulmonary hypertension. | Citation | 18024717 (PMID)
10.1152/ajplung.00034.2007 (DOI) |
Boyle S, Shioda T, Perantoni AO, de Caestecker M. Cited1 and Cited2 are differentially expressed in the developing kidney but are not required for nephrogenesis. (2007) Dev Dyn 236: 2321-30
Show Abstract · Added January 5, 2011Early kidney development in mammals is characterized by reciprocal tissue interaction between the ureteric bud and the metanephric mesenchyme. The coordinated response to this interaction is regulated largely at the transcriptional level. Here, we investigate the expression and function of Cited1, a transcriptional cofactor that we have previously implicated in kidney development. We show that Cited1 is expressed in the metanephric mesenchyme after invasion of the ureteric bud and that its expression is limited to the cap mesenchyme, those cells that aggregate most tightly around the tip of the ureteric bud and give rise to nephronic epithelium of the adult kidney. Cited1 is down-regulated during the initial stages of epithelial conversion and is not expressed past this progenitor stage. Despite its unique expression pattern, deletion of Cited1 does not disrupt kidney development. We hypothesized that this finding was due to functional redundancy with other members of this gene family. The expression pattern of Cited2 overlaps that of Cited1, but its deletion, either alone or in combination with Cited1, does not disrupt epithelial differentiation of the metanephric mesenchyme. From these studies, we conclude that Cited1 and 2 are dynamically expressed during kidney development, but are not required for nephrogenesis. | Citation | 17615577 (PMID)
10.1002/dvdy.21242 (DOI) |
Frank DB, Abtahi A, Yamaguchi DJ, Manning S, Shyr Y, Pozzi A, Baldwin HS, Johnson JE, de Caestecker MP. Bone morphogenetic protein 4 promotes pulmonary vascular remodeling in hypoxic pulmonary hypertension. (2005) Circ Res 97: 496-504
Show Abstract · Added January 5, 2011We show that 1 of the type II bone morphogenetic protein (BMP) receptor ligands, BMP4, is widely expressed in the adult mouse lung and is upregulated in hypoxia-induced pulmonary hypertension (PH). Furthermore, heterozygous null Bmp4(lacZ/+) mice are protected from the development of hypoxia-induced PH, vascular smooth muscle cell proliferation, and vascular remodeling. This is associated with a reduction in hypoxia-induced Smad1/5/8 phosphorylation and Id1 expression in the pulmonary vasculature. In addition, pulmonary microvascular endothelial cells secrete BMP4 in response to hypoxia and promote proliferation and migration of vascular smooth muscle cells in a BMP4-dependent fashion. These findings indicate that BMP4 plays a dominant role in regulating BMP signaling in the hypoxic pulmonary vasculature and suggest that endothelium-derived BMP4 plays a direct, paracrine role in promoting smooth muscle proliferation and remodeling in hypoxic PH. | Citation | 16100039 (PMID)
10.1161/01.RES.0000181152.65534.07 (DOI) |
Plisov S, Tsang M, Shi G, Boyle S, Yoshino K, Dunwoodie SL, Dawid IB, Shioda T, Perantoni AO, de Caestecker MP. Cited1 is a bifunctional transcriptional cofactor that regulates early nephronic patterning. (2005) J Am Soc Nephrol 16: 1632-44
Show Abstract · Added January 5, 2011In a screen to identify factors that regulate the conversion of mesenchyme to epithelium during the early stages of nephrogenesis, it was found that the Smad4-interacting transcriptional cofactor, Cited1, is expressed in the condensed cap mesenchyme surrounding the tip of the ureteric bud (UB), is downregulated after differentiation into epithelia, and has the capacity to block UB branching and epithelial morphogenesis in cultured metanephroi. Cited1 represses Wnt/beta-catenin but activates Smad4-dependent transcription involved in TGF-beta and Bmp signaling. By modifying these pathways, Cited1 may coordinate cellular differentiation and survival signals that regulate nephronic patterning in the metanephros. | Citation | 15843474 (PMID)
10.1681/ASN.2004060476 (DOI) |
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