Biomedical subjects

Saverio Bellusci

Publications and source records attributed to Saverio Bellusci.

24 records · Page 2Linked to original sources

PubMed2004

Fibroblast growth factor receptor 2 IIIb invalidation--a potential cause of familial duodenal atresia.

BACKGROUND/PURPOSE: Duodenal atresia (DA) occurs in 1 in every 6,000 live births and represents a significant surgically correctable cause of intestinal obstruction in the neonate. Familial or congenital DA has been reported, implying that at least some cases of DA are the result of genetic, heritable abnormalities. The genes controlling duodenal development are incompletely understood. Fibroblast growth factor receptor 2IIIb (Fgfr2b) is known to play a critical role in the development of multiple organ systems including other gastrointestinal tract (GIT) structures. This study shows the key role of Fgfr2b in normal duodenal development and the pathogenesis of DA. METHODS: Wild type (Wt) and Fgfr2b-/- embryos were harvested from timed pregnant mothers at stage E18.5 and were analyzed for duodenal phenotype. RESULTS: Inactivation of Fgfr2b results in DA. DA is present in the Fgf2b-/- mutants with a 35% penetrance. The duodenal phenotype of the Fgf2b-/- mutants ranges from normal to a mucosal web, type I, and type III atresia. CONCLUSIONS: Fgfr2b is a critical regulatory gene in the development of the duodenum. Fgfr2b invalidation (Fgfr2b-/- mutant) results in a reproducible, autosomal recessive duodenal atresia phenotype with incomplete penetrance and a variable phenotype.

Animals↗

PubMed2004

The molecular genetics of lung morphogenesis and injury repair.

Lung development, as well as epithelial injury repair, is tightly coordinated by a fine balance between stimulatory versus inhibitory genes that appear to co-regulate the function of stem/progenitor cells in the lung. Recently, it has been noted that many of the same genes direct development of the respiratory organs (tracheae) in the fruit fly Drosophila as in mice and men. For example, FGF receptor tyrosine kinase signaling is essential for respiratory organogenesis in both fly and mouse and is negatively regulated by the sprouty genes, a family of inducible FGF pathway inhibitors. Additionally, FGF signaling is required for formation of new alveoli, protection of alveolar epithelial cells from injury, as well as migration and proliferation of putative alveolar stem/progenitor cells during lung repair. Conversely, TGFbeta receptor serine-threonine kinase signaling via Smads 2, 3 and 4 inhibits lung morphogenesis and can inhibit postnatal alveolar development, while excessive TGFbeta signaling via Smad3 causes interstitial fibrosis. On the other hand, BMP4 stimulates morphogenesis of intact embryonic lung, while inhibiting proliferation of isolated epithelium. We speculate that evolutionary-developmental, functional conservation of the FGF- FGFR-SPROUTY stimulatory pathway as well as of the TGFbeta/BMP-SMAD modulatory pathways identifies them as potential therapeutic targets for rational therapy. Novel therapy to activate lung stem/progenitor cells, ameliorate lung injury, augment lung repair and/or induce lung regeneration could be highly beneficial in both children and adults with intractable pulmonary insufficiency.

Animals↗

PubMed2003

Functional analysis of the human Sprouty2 gene promoter.

Sprouty2 plays a key role in negatively modulating the fibroblast growth factor signaling pathway, which is required for early branching events in embryonic development. The expression of the murine Sprouty2 gene shows a temporally and spatially restricted pattern in developing lung. In order to clarify the molecular mechanisms governing the transcription of the Sprouty2 gene, we first characterized the genomic organization of the human Sprouty2 (hSpry2) gene and mapped its transcription start sites by 5'-rapid amplification of cDNA ends. Subsequently, a 4-kb sequence from the 5'-flanking region of the gene was cloned and determined to contain promoter activity. Detailed truncation analysis of the hSpry2 promoter revealed the presence of context-specific suppressor activity in the distal upstream region. More importantly, we demonstrated that all the elements necessary to achieve strong basal transcription activity were located within the proximal 0.4-kb region. Sequence analysis revealed that this functionally important proximal region contains neither TATA nor CAAT box but an initiator element around the transcription start site. Several cis-acting elements (including AP2, CREB, SP1 and Ets-1) were found to be present in the proximal region, and their interactions with specific nuclear proteins were confirmed by electrophoretic mobility shift assays. To our knowledge, this is the first promoter study of any mammalian Sprouty gene. We propose that the high-level basal expression of hSpry2 is controlled by multiple transcription factors binding to its proximal promoter.

5' Flanking Region↗

PubMed2003

Growth factor signaling in lung morphogenetic centers: automaticity, stereotypy and symmetry.

Lung morphogenesis is stereotypic, both for lobation and for the first several generations of airways, implying mechanistic control by a well conserved, genetically hardwired developmental program. This program is not only directed by transcriptional factors and peptide growth factor signaling, but also co-opts and is modulated by physical forces. Peptide growth factors signal within repeating epithelial-mesenchymal temporospatial patterns that constitute morphogenetic centers, automatically directing millions of repetitive events during both stereotypic branching and nonstereotypic branching as well as alveolar surface expansion phases of lung development. Transduction of peptide growth factor signaling within these centers is finely regulated at multiple levels. These may include ligand expression, proteolytic activation of latent ligand, ligand bioavailability, ligand binding proteins and receptor affinity and presentation, receptor complex assembly and kinase activation, phosphorylation and activation of adapter and messenger protein complexes as well as downstream events and cross-talk both inside and outside the nucleus. Herein we review the critical Sonic Hedgehog, Fibroblast Growth Factor, Bone Morphogenetic Protein, Vascular Endothelial Growth Factor and Transforming Growth Factorbeta signaling pathways and propose how they may be functionally coordinated within compound, highly regulated morphogenetic gradients that drive first stereotypic and then non-stereotypic, automatically repetitive, symmetrical as well as asymmetrical branching events in the lung.

Aging↗

PubMed2003

Mouse embryonic mammogenesis as a model for the molecular regulation of pattern formation.

In this review we describe how mouse embryonic mammogenesis depends on a continuous communication between the epithelial and mesenchymal compartment of the mammary rudiment. Although the functions of only a few genes in the regulation of these epithelio-mesenchymal interactions during mouse mammary development are known so far, key roles are suggested for WNT, FGF and PTHrP signaling. However, the exact mechanism of action of these signaling pathways and their possible cross-talk in the induction of mammary development are not clear, nor does our current knowledge suffice to explain how the number and positions of the mammary rudiments are so well defined. Nonetheless, by the description of aberrant induction and/or maintenance of the mammary rudiments in a variety of inbred mouse strains and mutants, we have accumulated data demonstrating that the mammary rudiments develop independently of each other at these positions. In addition, each rudiment pair responds differently to altered levels of gene expression. This not only clarifies the unique identity of each placode, but the different molecular requirement of each placode also suggests that different molecular mechanisms may underlie the formation of such identical structures. For future investigations in the field, such a unique molecular identity of each mammary rudiment should be of critical concern.

Animals↗

PubMed2002

Role of FGF10/FGFR2b signaling during mammary gland development in the mouse embryo.

The mouse develops five pairs of mammary glands that arise during mid-gestation from five pairs of placodes of ectodermal origin. We have investigated the molecular mechanisms of mammary placode development using Lef1 as a marker for the epithelial component of the placode, and mice deficient for Fgf10 or Fgfr2b, both of which fail to develop normal mammary glands. Mammary placode induction involves two different signaling pathways, a FGF10/FGFR2b-dependent pathway for placodes 1, 2, 3 and 5 and a FGF10/FGFR2b-independent pathway for placode 4. Our results also suggest that FGF signaling is involved in the maintenance of mammary bud 4, and that Fgf10 deficient epithelium can undergo branching morphogenesis into the mammary fat pad precursor.

Animals↗