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ABSTRACT: Hoxa2 is required for a variety of developmental processes in the branchial arches and in the hindbrain. We have created a Hoxa2 allele that is about 45% as active in transcription as its wild-type counterpart. This allele, together with the Hoxa2 null and wild-type alleles, allowed the generation of embryos developing in the presence of different levels of Hoxa2 activity. Analysis of these embryos indicates that in general the hindbrain is more resistant to Hoxa2 deficiencies than the second branchial arch. Also, within the second arch, proximo-caudal areas are more sensitive than the rostro-distal. In the hindbrain, basic segmentation and patterning processes seem to occur normally at Hoxa2 levels as low as 20% of the normal. In addition, specific neuronal markers along the dorso-ventral axis of the hindbrain seem differentially affected by reduced Hoxa2 levels. These results provide new clues to understand the role of Hoxa2 in the different embryonic areas where it is required.
Mechanisms of Development 11/2001; 108(1-2):135-47. · 2.83 Impact Factor
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ABSTRACT: OTX2, a homeodomain protein essential in mouse for the development of structures anterior to rhombomere 3, binds with high affinity to a DNA element (called OTS) present in the human tenascin-C promoter. Here we investigate the binding properties of the full length recombinant human OTX2 and of several deletion mutants to the OTS element. We demonstrate that, upon binding of the protein to its DNA target site, a second molecule of OTX2 is recruited to the complex and that a nearby second binding site is not necessary for this interaction. OTX2 sequences located within a region carboxyl-terminal to the homeodomain are necessary in addition to the homeodomain for binding to DNA. Furthermore, OTX2 dimerization requires the same protein domains necessary for DNA binding.
FEBS Letters 03/1999; 445(1):160-4. · 3.54 Impact Factor
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R Pontremoli,
A Sofia,
A Tirotta,
M Ravera,
C Nicolella,
F Viazzi,
G P Bezante,
L Borgia, N Bobola,
R Ravazzolo,
G Sacchi,
G Deferrari
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ABSTRACT: The activity of the renin-angiotensin-aldosterone system is thought to play a significant role in the development of target organ damage in essential hypertension. An insertion/deletion (I/D) polymorphism of the angiotensin I-converting enzyme (ACE) gene has recently been associated with increased risk for left ventricular hypertrophy and coronary heart disease in the general population. The D allele is associated with higher levels of circulating ACE and therefore may predispose to cardiovascular damage. The study presented here was performed to investigate the association between the ACE genotype, microalbuminuria, retinopathy, and left ventricular hypertrophy in 106 patients with essential hypertension. ACE gene polymorphism was determined by polymerase chain reaction technique. Microalbuminuria was evaluated as albumin-to-creatinine ratio (A/C) in three nonconsecutive first morning urine samples (negative urine culture) after a 4-wk washout period. Microalbuminuria was defined as A/C between 2.38 to 19 (men) and 2.96 to 20 (women). Hypertensive retinopathy was evaluated by direct funduscopic examination (keith-Wagener-Barker classification) and left ventricular hypertrophy by M-B mode echocardiography. The distribution of the DD, ID, and II genotypes was 27, 50, and 23%, respectively. The prevalence of microalbuminuria, retinopathy, and left ventricular hypertrophy was 19, 74, and 72% respectively. There were no differences among the three genotypes for age, known duration of disease, body mass index, blood pressure, serum glucose, uric acid, and lipid profile. DD and ID genotypes were significantly associated with the presence of microalbuminuria (odds ratio, 8.51; 95% confidence interval, 1.07 to 67.85; P = 0.019), retinopathy (odds ratio, 5.19; 95% confidence interval, 1.71 to 15.75; P = 0.005) and left ventricular hypertrophy (odds ratio, 5.22; 95% confidence interval, 1.52 to 17.94; P = 0.016). Furthermore, patients with DD and ID genotypes showed higher levels of A/C (3.6 +/- 0.9, DD; 2.6 +/- 0.7, ID; 0.9 +/- 0.2 mg/mmol, II; P = 0.0015 by analysis of variance) and increased left ventricular mass index (152 +/- 4.7, DD + ID versus 133 +/- 5.7 g/m2, II; P = 0.01) compared with II patients. The D allele was significantly more frequent in patients with microalbuminuria (odds ratio, 2.59; 95% confidence interval, 1.24 to 5.41; P = 0.013) and in those with retinopathy (odds ratio, 2.44; 95% confidence interval, 1.21 to 4.90; P = 0.015). Multiple regression analyses performed among the entire cohort of patients demonstrated that ACE genotype significantly and independently influences the presence of retinopathy, left ventricular hypertrophy, and microalbuminuria. In conclusion, the D allele of the ACE gene is associated with microalbuminuria as well as with retinopathy and left ventricular hypertrophy, and seems to be an independent risk factor for target organ damage in essential hypertension.
Journal of the American Society of Nephrology 01/1997; 7(12):2550-8. · 9.66 Impact Factor
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ABSTRACT: Cell division in haploid yeast gives rise to a "mother" cell capable of mating-type switching and a "daughter" cell that is not. Switching is initiated by the HO endonuclease, whose gene is only transcribed in cells that have previously given birth to a bud (mother cells). HO expression depends on a minimyosin, She1p/Myo4p, which accumulates preferentially in growing buds. We describe a gene, ASH1, that is necessary to repress HO in daughters. ASH1 encodes a zinc finger protein whose preferential accumulation in daughter cell nuclei at the end of anaphase depends on She1p/Myo4p. The greater abundance of Ash1p in daughter cells is responsible for restricting HO expression to mother cells.
Cell 04/1996; 84(5):699-709. · 32.40 Impact Factor
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ABSTRACT: Interphotoreceptor retinoid-binding protein (IRBP) is the major protein component of the interphotoreceptor matrix. IRBP has a highly restricted tissue-specific expression in retinal photoreceptor cells and in a subgroup of pinealocytes. With the purpose of understanding how transcriptional regulation contributes to the expression of human IRBP, we have studied a short promoter fragment (from -123 to +18, relative to the transcription start site). We demonstrate, by analysis of the expression of the lacZ reporter gene fused to this short promoter fragment in transgenic mice, that it is sufficient to confer tissue-specific expression in retinal photoreceptors and in pinealocytes. DNA/protein binding assays, performed to identify binding sites for tissue-specific trans-acting factors, have shown that an element between -45 and -58 binds a factor present only in nuclear extracts of retinoblastoma-derived cell lines, which express IRBP. An element further upstream, between -86 and -106, binds apparently ubiquitous factors. Site-directed mutagenesis was performed to disrupt a GATTAA motif included in the -45 to -58 binding site and a second inverted GATTAA motif present shortly upstream. In transgenic mice bearing the mutated version of the promoter fragment, the expression of the reporter gene was completely abolished, thus suggesting that this element is essential for tissue-specific expression. A GATTAA motif appears in the 5'-flanking regions of several photoreceptor-specific genes, suggesting that this could be the recognition site for a photoreceptor-specific factor.
Journal of Biological Chemistry 02/1995; 270(3):1289-94. · 4.77 Impact Factor
