Early Postnatal Lethality inHoxa-5Mutant Mice Is Attributable to Respiratory Tract Defects

Aubin, Josée; Lemieux, Margot; Tremblay, Michel G.; Bérard, J; Jeannotte, Lucie

doi:10.1006/dbio.1997.8746

Cited by 177 publications

(196 citation statements)

References 52 publications

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“…In Situ Hybridization-Conditions were adapted from Aubin et al (25) and Rausa et al (26). FTF riboprobes were generated from a 1.2-kb ClaI/HindIII mFTF cDNA fragment (nt 661-1856 in Ref.…”

Section: Methodsmentioning

confidence: 99%

The Fetoprotein Transcription Factor (FTF) Gene Is Essential to Embryogenesis and Cholesterol Homeostasis and Is Regulated by a DR4 Element

Paré

Malenfant

Courtemanche

et al. 2004

Journal of Biological Chemistry

145

134

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Development of the mammalian embryo relies upon nutritive functions fulfilled by the visceral endoderm and then by the liver (1). A part of these functions is accomplished by nutrient carrier proteins of the albumin gene family, a multigene locus expressed by the liver and subject to precise developmental controls. One albumin-related gene, the ␣ 1 -fetoprotein (AFP) 1 gene, is activated at the onset of liver differentiation and operates tightly coupled with liver growth (2, 3). In 1988, our group circumscribed a proximal AFP promoter element essential to AFP gene activity in hepatocytes, and distinct from promoter components regulating the other albumin loci (4). The AFP-specific activator was then identified as orphan receptor fetoprotein transcription factor (5-7), so named for its first identified target locus (genome data base nomenclature, 2 NR5A2 in the nuclear receptor nomenclature, Ref. 9); also referred to as LRH1 or CPF). FTF belonged to a primitive class of nuclear receptors and emerged as a critical lead to connect AFP gene activation with early embryonic growth and differentiation processes.Subsequent studies indicated that developmental FTF functions even preceded its activation of the AFP locus in hepatocytes. In situ hybridization analysis in the mouse at embryonic day 8 -9 showed abundant FTF transcripts in the foregut endoderm, before liver morphogenesis (10). Characterization of the FTF gene promoter also revealed a cluster of regulatory motifs conserved in distant species and potential targets of cell lineage specification factors (11). Among these were three proximal binding sites for GATA factors, known to be essential for visceral endoderm function (12, 13). Furthermore, three HNF genes important to liver differentiation, HNF1␣, HNF4␣, and HNF3␤, were found to each contain double FTF-binding sites in their proximal promoter and to be activated by FTF in transfection assays (11). Thus, a pivotal role was suggested for FTF in a transcriptional cascade using determination factors to activate FTF in prehepatic endodermal cells, and then using FTF to drive AFP and other effectors of the hepatic program.

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“…In Situ Hybridization-Conditions were adapted from Aubin et al (25) and Rausa et al (26). FTF riboprobes were generated from a 1.2-kb ClaI/HindIII mFTF cDNA fragment (nt 661-1856 in Ref.…”

Section: Methodsmentioning

confidence: 99%

The Fetoprotein Transcription Factor (FTF) Gene Is Essential to Embryogenesis and Cholesterol Homeostasis and Is Regulated by a DR4 Element

Paré

Malenfant

Courtemanche

et al. 2004

Journal of Biological Chemistry

145

134

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“…26 The analysis of the Hoxa5 mutant mouse line has revealed the preponderant role of this gene in lung development and maturation. 27,28 The loss of Hoxa5 function severely compromises viability at birth because of trachea and lung dysmorphogenesis. Moreover, the Hoxa5 mutation affects the embryonic expression of epithelial regulators of lung development and function, such as the Nkx2.1, Foxa2, and N-myc genes.…”

Section: Hoxa5mentioning

confidence: 99%

“…27 Surviving adult mutants present a severe emphysemalike phenotype characterized by enlarged airspaces and an overall decrease in septa number. 28 On macroscopic examination, some areas of Hoxa5 Ϫ/Ϫ lungs were completely depleted of alveoli, whereas others showed large tubular structures (shown for P31; Figure 1, K and L).…”

Section: Abnormal Lung Morphology In Hoxa5mentioning

confidence: 99%

Impact of the Loss of Hoxa5 Function on Lung Alveogenesis

Mandeville

Aubin

LeBlanc

et al. 2006

The American Journal of Pathology

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The involvement of genes controlling embryonic processes in the etiology of diseases often escapes attention because of the focus given to their inherent developmental role. Hoxa5 belongs to the Hox gene family encoding transcription factors known for their role in skeletal patterning. Hoxa5 is required for embryonic respiratory tract morphogenesis. We now show that the loss of Hoxa5 function has severe repercussions on postnatal lung development. Hoxa5؊/؊ lungs present an emphysema-like morphology because of impaired alveogenesis. Chronic inflammation characteristics, including goblet cell hyperplasia, mucus hypersecretion, and recruitment of inflammatory cells, were also observed. Altered cell specification during lung morphogenesis triggered goblet cell anomalies. In addition, the defective motility of alveolar myofibroblast precursors in the embryonic lung led to the mispositioning of the alveolar myofibroblasts and to abnormal elastin deposition postnatally. Both goblet cell hyperplasia and elastic fiber abnormalities contributed to the chronic physiopathological features of Hoxa5 ؊/؊ lungs. They constituted an attractive stimulus to recruit activated macrophages that in turn generated a positive feedback loop that perpetuated macrophage accumulation in the lung. The present work corroborates the notion that altered Hox gene expression may predispose to lung pathologies. Lung morphogenesis relies on finely orchestrated processes that initiate from the outpocketing and the elongation of the foregut endoderm into the surrounding mesenchyme. The lung bud then branches extensively giving rise to saccules that expend and subdivide to ultimately produce alveoli. In the mouse, the main stem bronchi form at approximately embryonic day (E) 9.5, and ramification organized by signaling centers shapes the respiratory tree during the pseudoglandular period that extends from E14.0 to E16.5. At late gestational stages, saccules are found at the end of each terminus of the pulmonary tree. The last step of lung morphogenesis occurs between postnatal day (P) 5 and P30, and it aims at multiplying the respiratory surface for vital gas exchanges after birth by modifying the distal lung architecture through the process of alveogenesis. During each step of lung development, the concerted action of transcriptional regulators, signaling molecules, their associated receptors and downstream effectors governs branching morphogenesis and lung maturation by integrating cellular proliferation, differentiation, apoptosis, and migration.

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“…The evidence for an important role of Hoxa5 in development comes mainly from the study of the Hoxa5 knock-out mice (9,10). The resultant heterozygous mutant mice were viable and indistinguishable from their wild type littermates.…”

mentioning

confidence: 99%

“…However, more than 60% of the homozygous pups died within 4 days of birth. In homozygous newborn mutants, improper tracheal and lung morphogenesis lead to tracheal occlusion and to respiratory distress associated with a marked decrease in the production of surfactant protein (10). Loss of Hoxa5 also perturbed intestinal maturation and transiently affects thyroid development (11,12).…”

mentioning

confidence: 99%

Identification of Transcriptional Targets of HOXA5

Chen

Rubin

Zhang

et al. 2005

Journal of Biological Chemistry

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The homeobox gene HOXA5 encodes a transcription factor that has been shown to play important roles in embryogenesis, hematopoiesis, and tumorigenesis. In order to decipher downstream signaling pathways of HOXA5, we utilized oligonucleotide microarray analysis to identify genes that are differentially expressed in HOXA5-induced cells compared with uninduced cells. Comparative analysis of gene expression changes after 9 h of HOXA5 induction in Hs578T breast cancer cells identified 306 genes whose expression was modulated at least 2-fold. Ten of these 306 genes were also up-regulated by at least 2-fold at 6 h post-induction. The expression of all of these 10 genes was confirmed by semiquantitative reverse transcription-PCR. Among these 10 genes, which are most likely to be direct targets of HOXA5, we initiated an investigation into the pleiotrophin gene by first cloning its promoter. Transient transfection assays indicated that HOXA5 can specifically activate the pleiotrophin promoter. Promoter deletion, chromatin immunoprecipitation assay, and gel-shift assays were performed to show that HOXA5 can directly bind to one binding site on the pleiotrophin promoter. These data strongly suggest that microarray analysis can successfully identify many potential direct downstream genes of HOXA5. Further functional analysis of these targets will allow us to better understand the diverse functions of HOXA5 in embryonic development and tumorigenesis.

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Early Postnatal Lethality inHoxa-5Mutant Mice Is Attributable to Respiratory Tract Defects

Cited by 177 publications

References 52 publications

The Fetoprotein Transcription Factor (FTF) Gene Is Essential to Embryogenesis and Cholesterol Homeostasis and Is Regulated by a DR4 Element

The Fetoprotein Transcription Factor (FTF) Gene Is Essential to Embryogenesis and Cholesterol Homeostasis and Is Regulated by a DR4 Element

Impact of the Loss of Hoxa5 Function on Lung Alveogenesis

Identification of Transcriptional Targets of HOXA5

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