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PubMedDate not supplied

Effects of calcium channel blockade on mammalian lung branching morphogenesis.

The bronchial tree is formed during the pseudo-glandular stage of lung development in a process termed lung branching morphogenesis. Coinciding with the period of lung branching morphogenesis is the appearance of spontaneous airway contractions, a phenomenon whose role in development remains unclear. In this study, an in vitro model of murine lung branching morphogenesis was used to examine the potential role of airway contractions in airway branching and lung growth. Spontaneous airway contractions of the proximal airways were observed in cultured murine lungs (obtained at 11 days of gestation) after 48 h in culture. Airway contractility was inhibited in a reversible manner by the voltage-dependent calcium channel blocker Nifedipine. Interestingly, long-term incubation of lung rudiments with Nifedipine not only prevented airway contraction, but also caused lung hypoplasia. The Nifedipine-treated hypoplastic lungs showed a normal branching pattern, suggesting that airway contractions and calcium channel function are not necessary for cleft formation directly. These observations suggest that calcium ion transport is necessary for development of airway contractions and for normal progression of lung growth.

Animals↗
PubMed2026

CD109 exhibits a dynamic expression pattern in coronary endothelium and endocardial-derived valve mesenchyme during heart development with preserved morphogenesis following endothelial-specific deletion.

BACKGROUND: CD109 encodes a GPI-linked glycoprotein that acts as a signaling modulator in the TGF-β pathway. CD109 has emerged in several genome-wide association studies as linked to coronary artery disease, myocardial infarction, and angina pectoris. Heterozygous loss-of-function mutations in CD109 have also been reported in patients with congenital heart defects, suggesting potential developmental relevance, though CD109 has never been investigated in the context of cardiovascular development. We previously identified Cd109 upregulation in murine atrioventricular valves undergoing myxomatous degeneration following a reduction of epicardial-derived cells. Here, we characterize Cd109 expression in the murine cardiovascular system and assess its function during development using in vitro and in vivo approaches. RESULTS: We found that Cd109 is strongly expressed in the endothelium of the coronary vasculature and in endocardial-derived subpopulations in the atrioventricular valves. This expression persists through key stages in cardiovascular development. Western blotting and immunostaining confirm endothelial expression in heart and lung tissues. siRNA-mediated knockdown of CD109 in primary human endothelial cells led to dysregulation of vascular development pathways and decreased tube formation capacity. We generated endothelial-specific Cd109 knockout mice, eliminating Cd109 expression from heart and lung tissues without overt consequences for atrioventricular valve or coronary vascular morphogenesis during heart development. CONCLUSION: CD109 exhibits a highly dynamic spatiotemporal expression pattern during cardiovascular development, with enriched expression in coronary endothelial cells and endocardial-derived subpopulations in the valves. Despite this striking developmental expression pattern, previously reported human genetic associations with cardiovascular diseases, and endothelial-associated phenotypes following siRNA-mediated CD109 knockdown in a primary human endothelial cell line, endothelial/endocardial-lineage deletion of Cd109 did not produce overt abnormalities in atrioventricular valve or coronary vascular morphogenesis during embryonic development. Collectively, these findings identify CD109 as a useful marker of coronary endothelial and endocardial-derived valve cell populations and suggest that CD109 may function in a context-dependent or modulatory manner rather than as an essential regulator of cardiovascular morphogenesis under normal developmental conditions.

CD109↗
PubMed2000

FGF/FGFR-2(IIIb) signaling is essential for inner ear morphogenesis.

Interactions between FGF10 and the IIIb isoform of FGFR-2 appear to be crucial for the induction and growth of several organs, particularly those that involve budding morphogenesis. We determined their expression patterns in the inner ear and analyzed the inner ear phenotype of mice specifically deleted for the IIIb isoform of FGFR-2. FGF10 and FGFR-2(IIIb) mRNAs showed distinct, largely nonoverlapping expression patterns in the undifferentiated otic epithelium. Subsequently, FGF10 mRNA became confined to the presumptive cochlear and vestibular sensory epithelia and to the neuronal precursors and neurons. FGFR-2(IIIb) mRNA was expressed in the nonsensory epithelium of the otocyst that gives rise to structures such as the endolymphatic and semicircular ducts. These data suggest that in contrast to mesenchymal-epithelial-based FGF10 signaling demonstrated for other organs, the inner ear seems to depend on paracrine signals that operate within the epithelium. Expression of FGF10 mRNA partly overlapped with FGF3 mRNA in the sensory regions, suggesting that they may form parallel signaling pathways within the otic epithelium. In addition, hindbrain-derived FGF3 might regulate otocyst morphogenesis through FGFR-2(IIIb). Targeted deletion of FGFR-2(IIIb) resulted in severe dysgenesis of the cochleovestibular membraneous labyrinth, caused by a failure in morphogenesis at the otocyst stage. In addition to the nonsensory epithelium, sensory patches and the cochleovestibular ganglion remained at a rudimentary stage. Our findings provide genetic evidence that signaling by FGFR-2(IIIb) is critical for the morphological development of the inner ear.

Animals↗
PubMed2002

Role of hlx1 in zebrafish brain morphogenesis.

hlx1 is a related homeobox gene expressed in a dynamic spatiotemporal expression pattern during development of the zebrafish brain. The homologues of hlx1, mouse dbx1 and Xenopus Xdbx, are known to play a role in the specification of neurons in the spinal cord. However, the role of these molecules in the brain is less well known. We have used two different approaches to elucidate a putative function for hlx1 in the developing zebrafish brain. Blastomeres were injected with either synthetic hlx1 mRNA in gain-of-function experiments or with antisense morpholino oligonucleotides directed against hlx1 in loss-of-function experiments. Mis-expression of hlx1 produced severe defects in brain morphogenesis as a result of abnormal ventricle formation, a phenotype we referred to as "fused-brain". These animals also showed a reduction in the size of forebrain neuronal clusters as well as abnormal axon pathfinding. hlx1 antisense morpholinos specifically perturbed hindbrain morphogenesis leading to defects in the integrity of the neuroepithelium. While hindbrain patterning was in the most part unaffected there were select disruptions to the expression pattern of the neurogenic gene Zash1B in specific rhombomeres. Our results indicate multiple roles for hlx1 during zebrafish brain morphogenesis.

Animals↗
PubMed2003

Glial cell-induced endothelial morphogenesis is inhibited by interfering with extracellular signal-regulated kinase signaling.

PURPOSE: Tumor vasculature provides the infrastructure by which malignant tissue can be nourished; therefore, targeting angiogenesis may be an effective means of treating cancer. We showed previously that SNB19 glioblastoma cells modulate bovine retinal endothelial cells in cocultures to form capillary-like network structures, that matrix metalloproteinase-9 (MMP-9) expression is critical for endothelial morphogenesis, and that MMP-9 expression in glioblastoma cells is regulated by extracellular signal-regulated kinase-1 (ERK-1). In the present study, we investigated whether interfering with the activation of this mitogen-activated protein (MAP) kinase would repress MMP-9 synthesis and inhibit capillary formation. EXPERIMENTAL DESIGN: Cocultures of bovine retinal endothelial and SNB19 cells were analyzed for MMP-9 secretion, and phospho- and total ERK levels. These cocultures were treated with PD98059, a specific inhibitor of MAP/ERK kinase 1, or transfected with dominant-negative ERK-1 mutant containing expression vector. Alterations in capillary-like structure formation, and actin cytoskeleton and secretion of vascular endothelial growth factor (VEGF), MMP-9, and tissue inhibitor of metalloproteinase-1 were determined by immunofluorescence, gelatin zymography, and Western blotting. RESULTS: We found that inhibition of the ERK-1/2 pathway with PD98059 abrogated glial cell-mediated capillary formation by the endothelial cells and reduced the levels of MMP-9 in the coculture. Strikingly, the abrogation of MAP kinase signaling by a dominant-negative ERK-1 mutant inhibited glial-induced capillary network formation by reducing VEGF levels and MMP-9 activity and increasing the levels of tissue inhibitor of metalloproteinase-1. Inhibition of ERK activity also disrupted the formation of the actin cytoskeleton, a prerequisite for endothelial cell migration. CONCLUSION: The mechanism underlying activation of ERK is involved in reorganization of the actin cytoskeleton, and induction of VEGF and MMP-9, thereby stimulating endothelial cell morphogenesis. These studies clearly provide experimental evidence that ERK inhibition diminishes glial-induced endothelial-cell morphogenesis; therefore, interfering with ERK signaling may be a viable approach to target angiogenesis.

Actins↗
PubMed2005

[Gene expression profiling of microvascular endothelial cells during capillary morphogenesis in an in vitro model of angiogenesis].

OBJECTIVE: To globally compare the gene expression profiles during the capillary morphogenesis of human microvascular endothelial cells (HMVECs) in an in vitro angiogenesis system with Affymetrix oligonucleotide array. METHODS: A microcarrier-based in vitro angiogenesis system was developed, in which endothelial cells (ECs) migrated into the matrix, proliferated, and formed capillary sprouts. The sprouts elongated, branched and formed network. The total RNA samples from the HMVECs at the selected time points (0.5 h, 24 h, and 72 h) during the capillary morphogenesis were used for microarray analyses, and the data were processed with the software provided by the manufactory. The expression patterns of some genes were validated and confirmed by Semi-quantitative RT-PCR. The regulated genes were grouped based on their molecular functions and expression patterns, and among them the expression of chemokines/chemokine receptors were specially examined and their functional implications were analyzed. RESULTS: About 1500 genes were found up- or down- regulated 2-folds or above detected by the arrays, and among them, about 400 genes regulated 3-folds or above. The regulated genes could be grouped into categories based on their molecular functions such as growth factor and receptor, cell proliferation, extracellular matrix, cell cycle and apoptosis, signaling molecule and transcription factor, and so on, using the Gene Ontology Mining Tool in The NetAffx Analysis Center. The regulated genes were also clustered into six groups based on their patterns of expression. As for chemokines, the CCL2/MCP-1, CCL5/RANTES and CX3CL1 were identified to be specially upregulated at 24 h time point when the sprouting characterized the morphological change. It was thus suggested that they might exert crucial roles at the early stage of angiogenesis. CONCLUSIONS: Based on our angiogenesis model, and by oligonucleotide arrays, the present study demonstrates global profiles of the gene expression during endothelial capillary morphogenesis, and the results provide us much information about the molecular mechanisms of angiogenesis, with which further evaluation of individual genes can be encouraged.

Capillaries↗
PubMed2025

A model for boundary-driven tissue morphogenesis.

Tissue deformations during morphogenesis can be active, driven by internal processes, or passive, resulting from stresses applied at their boundaries. Here, we introduce the Drosophila hindgut primordium as a model for studying boundary-driven tissue morphogenesis. We characterize its deformations and show that its complex shape changes can be a passive consequence of the deformations of the active regions of the embryo that surround it. First, we find an intermediate characteristic triangular shape in the 3D deformations of the hindgut. We construct a minimal model of the hindgut primordium as an elastic ring deformed by active midgut invagination and germ band extension on an ellipsoidal surface, which robustly captures the symmetry-breaking into this triangular shape. We then quantify the 3D kinematics of the tissue by a set of contours and discover that the hindgut deforms in two stages: an initial translation on the curved embryo surface followed by a rapid breaking of shape symmetry. We extend our model to show that the contour kinematics in both stages are consistent with our passive picture. Our results suggest that the role of in-plane deformations during hindgut morphogenesis is to translate the tissue to a region with anisotropic embryonic curvature and show that uniform boundary conditions are sufficient to generate the observed nonuniform shape change. Our work thus provides a possible explanation for the various characteristic shapes of blastopore-equivalents in different organisms and a framework for the mechanical emergence of global morphologies in complex developmental systems.

Journal Article↗
PubMed1993

[Arterial distribution and morphogenesis of human maxilla].

There are two leading hypotheses concerning maxillofacial morphogenesis in human (Fusion Hypothesis & Overlapping Hypothesis). Differing opinions about the maxillary morphogenesis lead to different concepts about the intrinsic arterial supply to the maxilla. This research was to study the arterial constitution of human maxilla so as to inquire into its morphogenetic patterns. Appropriately perfused (Pb3O4 + turpentine) infraorbital and posterior superior alveolar arteries in 9 fresh human cadavers with ages ranging from 2 days to 35 years revealed that 4 individuals' arterial systems of maxilla consisted of anterior and posterior superior alveolar arteries, but the other 5 ones consisted only of the posterior superior alveolar artery, which extending to the facial midline and supplies all the incisor and molar teeth. The results indicated that two kinds of maxillary morphogenesis patterns may exist simultaneously.

Adult↗
PubMed1996

Differential expression of integrin alpha subunits supports distinct roles during lung branching morphogenesis.

Epithelial branching morphogenesis is a process by which a continuous epithelium, embedded in mesenchyme, forms tubules that extend and branch into the surrounding mesenchyme. The morphogenetic process is responsible for the architecture of many organs including the lung. Proper expression and function of extracellular matrix (ECM) molecules, such as collagens and laminins, are necessary for branching to occur normally. However, little is known about the role of epithelial cell surface molecules that mediate epithelial-matrix interactions during this process. We have studied the expression patterns of cell surface collagen and laminin integrin receptor alpha subunits, alpha 1, alpha 2, alpha 3, and alpha 6, in relation to that of collagen and laminin during lung branching morphogenesis. The alpha 1 integrin subunit was present on endothelia and smooth muscles around airways and large blood vessels. The mesenchyme expressed high levels of alpha 2 and alpha 6 but not alpha 3, whereas the epithelium expressed all three integrin subunits. In contrast to the widespread epithelial expression of alpha 3 and alpha 6, the epithelial expression of alpha 2 was restricted to branch tips. By performing in situ hybridization and immunofluorescence on serial sections, we found that alpha 2 protein expression on the epithelium correlated spatially and temporally with high level expression of collagen IV and laminin-1 mRNAs, suggesting that the alpha 2-expressing epithelial cells were in the process of producing and assembling their collagen and laminin matrices. While the expression of alpha 3 and alpha 6 on all lung epithelia suggests that these integrins may be important to lung epithelial development, the unique expression pattern of the alpha 2 subunit suggests that the alpha 2 beta 1 integrin may be important at branch tips either in the process of collagen/laminin synthesis and assembly or extension of the epithelial tubules into the mesenchyme.

Animals↗
PubMed1998

VEGF enhances pulmonary vasculogenesis and disrupts lung morphogenesis in vivo.

Vascular endothelial growth factor (VEGF) was expressed in developing respiratory epithelial cells under control of the promoter from the human surfactant protein C (SP-C) gene. SP-C-VEGF transgenic mice did not survive after birth. When obtained by hysterectomy on embryonic day 15 (E15) or 17 (E17), abnormalities in the transgenic mice were confined to the lung and were correlated with the expression of transgene mRNA as revealed by in situ hybridization. On E15 and E17, marked abnormalities in lung morphogenesis were observed in transgenic mice. Lungs consisted of large dilated tubules with increased peritubular vascularity. The mRNA levels of the VEGF receptor, Flk-1, and the endothelial cell specific receptor tyrosine kinase, Tie-1, were increased in lung mesenchyme of the transgenic mice. The numbers of acinar tubules and the abundance of mesenchyme were decreased. Endogenous VEGF mRNA was expressed in the respiratory epithelial cells of the developing lungs, and the levels of VEGF mRNA were increased in the SP-C-VEGF transgenic mice. Although the normal pattern of immunostaining for SP-C and Clara cell secretory protein (CCSP) indicated that epithelial cell differentiation was relatively unaltered by the transgene, electron microscopic analysis revealed a lack of alveolar Type I cell differentiation at E18. Expression of VEGF in the developing respiratory epithelium of transgenic mice increased growth of the pulmonary blood vessels, disrupted branching morphogenesis of the lung and inhibited Type I cell differentiation.

Animals↗
PubMed1998

PDGF-A and PDGFR-alpha regulate tooth formation via autocrine mechanism during mandibular morphogenesis in vitro.

Platelet-derived growth factor A (PDGF-A) binding to the PDGF receptor alpha (PDGFR-alpha) mediates signal transduction processes related to DNA synthesis, cell migrations, cytodifferentiation, and wound healing. Recent studies indicate that PDGFR-alpha functions during cranial neural crest cell migrations and first branchial arch morphogenesis (Stephenson et al. [1991] Proc. Natl. Acad. Sci. USA 88:6-10; Morrison-Graham et al. [1992] Development 115:133-142; Hu et al. [1995] Int. J. Dev. Biol. 39:939-945; Soriano [1997] Development 124:2691-2700). The present studies were designed to test the hypothesis that PDGF-A, interacts with its cognate receptor PDGFR-alpha via an autocrine mechanism that regulates the timing, rates, and size of embryonic mouse tooth morphogenesis. Both PDGF-A and PDGFR-alpha transcripts were coordinately expressed in mandibular prominences prior to and during tooth formation using reverse transcriptase-polymerase chain reaction (RT-PCR). During the dental lamina stage, ligand and receptor were present in both enamel organ epithelium and adjacent mesenchymal cells. During the bud stage, ligand and receptor were localized mainly to the enamel organ epithelium. Exogenous PDGF-A at 20 ng/ml enhanced tooth development to reach the cap stage with increased tooth size (P < 0.05) using embryonic day (E)10 mandibular explants cultured in serumless, chemically defined medium. A significant increase in DNA synthesis was observed within enamel organ epithelium at E10+4 when the mandibular explants were treated with PDGF-A at 20 ng/ml. These data suggest that PDGF-A and its cognate receptor (PDGFR-alpha) regulate the size and stage of tooth development via an autocrine mechanism during odontogenesis in vitro.

Animals↗
PubMed1997

Developmental alterations in casein kinase 2 activity during the morphogenesis of quail secondary palate.

BACKGROUND: During the progression of avian secondary palate morphogenesis, the rate of cell proliferation declines, whereas the production and accumulation of extracellular matrices increases. To investigate the regulation of these events, we examined the quail secondary palate for the activity of casein kinase 2 (CK 2), a pleiotropic serine/threonine second messenger independent enzyme implicated in cell growth and differentiation. METHODS: Quail palatal shelves were dissected between days 5 and 9 of incubation, which is the period of palate morphogenesis in quail, and prepared either for light microscopic observations or homogenized, cleared by ultracentrifugation, and then subjected to fractionation on a MonoQ column by fast protein liquid chromatography and Western immunoblotting. RESULTS: Histological examination showed that the palatal shelves appeared on day 5 of incubation and approximated by day 8 of incubation. Fractionation of palate extract using a Mono-Q column revealed the presence of a major peak of phosvitin phosphotransferase activity which eluted with 0.5 M NaCl. This activity peak coincided with the presence of a 42 kDa subunit of CK 2 as determined by Western blotting with a CK 2 specific antibody. The CK 2 activity towards phosvitin was elevated on days 5 and 6 and then rapidly declined by day 9. The decrease in CK 2 activity did not correlate with a decrease in CK 2 protein during palate development indicating that the differential activity of the CK 2 enzyme observed during quail palate development may be due to post-translational modifications of the enzyme. A high positive correlation was found between the CK 2 phosphotransferase activity and both the proliferation index and DNA synthesis during palate development. CONCLUSION: On the basis of literature analysis and the results of the present study, it was suggested that the activity of CK 2 may be regulated along with protein kinase A to coordinate cell proliferation and the synthesis of extracellular matrices during palate development in quail.

Animals↗
PubMed1997

Study by scanning electron microscopy of the morphogenesis of three types of lingual papilla in the rat.

BACKGROUND: Many mammals have four different types of lingual papilla, namely filiform, fungiform, circumvallate, and foliate papillae, on the dorsal or lateral surface of the tongue. However, details of the morphogenesis of these lingual papillae have not been reported. We have investigated the changes in the three-dimensional ultrastructure that occur during the morphogenesis of filiform, fungiform, and circumvallate papillae in rats during fetal and postnatal development. METHODS: Tongues were removed from rat fetuses on days 12 (E12) and 16 (E16) of gestation from newborns (P0) and from juveniles on days 7 (P7) and 14 (P14), and 21 (P21) after birth. Scanning electron microscopy was used for all observations. RESULTS: In fetuses at E12, the rudiments of fungiform papillae could be observed as two rows of bulges that extended bilaterally and parallel to the median sulcus on the anterior half of the dorsal surface of the tongue. In fetuses at E16, the arrangement of the rudiments of fungiform papillae was relatively regular, with a latticelike pattern. At this stage, the outline of the rudiment of the circumvallate papilla could be recognized on the median line between the lingual body and the lingual radix. No rudiments of filiform papillae were visible. At P0, rudiments of filiform papillae were compactly distributed over the dorsal surface in the same way as in the adult. The width of these rudiments was about one-fourth that of fungiform papillae, and their tips were round as compared with those of filiform papillae in the adult. The fungiform and circumvallate papillae were large, and their outlines were somewhat irregular, as in the adult. In juveniles at P7, filiform papillae were long and slender. On the intermolar eminence, filiform papillar structures were quite large. A taste pore was clearly visible at the center of each fungiform papilla at this stage. The shape of the circumvallate papilla was similar to that in the adult. In juveniles at P14 and P21, the shapes of all three types of papilla were almost same as those in the adult. CONCLUSIONS: The rudiments of each of the three different kinds of lingual papilla appeared at a different respective stage of development in rats. The rudiments of the fungiform and circumvallate papillae, which are related to the sense of taste, were visible earlier than those of the filiform papillae, which are not involved in this sense.

Age Factors↗
PubMed1998

Photoreceptor morphogenesis in the human retina: a scanning electron microscopic study.

There are a number of scanning electron microscopic (SEM) studies on retinal photoreceptors of vertebrates. However, most of these are concerned with the adult retina, and only a very few deal with developing photoreceptors. In man, SEM studies have not been carried out on photoreceptor morphogenesis during fetal or postnatal stages. Hence, the present study was undertaken to examine the sequential morphological changes in developing photoreceptors during different gestational ages in the human retina. Retinas of human fetuses of gestational ages of 10-25 weeks and from autopsy of a 5-month-old infant were processed for SEM. The observations show some new information on the morphogenesis of photoreceptors. At 10-11 weeks, the outer and inner neuroblastic zones are well developed and separated from each other by the layer of Chievitz. By 15-16 weeks, the photoreceptor precursors appear as spherical inner segments on the scleral surface of the outer neuroblastic zone. Cilia develop as small protrusions from the apical ends of the inner segments. Photoreceptor inner segments become arranged in mosaic pattern by 18-19 weeks. In the mosaic, large cone inner segments (putative blue cones) stand out prominently from the remaining small cone inner segments (prospective red/green cones). The rod inner segments are identifiable and show cilia. Between 19-20 and 24-25 weeks, the cone inner segments elongate and change in shape from spherical to oval. At 24-25 weeks, the outer segments develop from the distal ends of rod cilia. At this period, the inner segments of rods and cones are interconnected by protoplasmic projections. Although the precursors of both rods and cones appear to be in a similar state of development at 14-15 weeks gestation, the rods undergo morphological maturation earlier than do the cones. Photoreceptor development in the anterior retina lags behind that of the posterior retina by about 10 weeks. At 5 months after birth, the posterior retina possesses fully developed photoreceptors that are comparable to those of the adult. However, the photoreceptors in the ora serrata resemble those in the posterior retina of 24-25 weeks gestation.

Fetus↗
PubMed1996

Sequential changes of programmed cell death in developing fetal mouse limbs and its possible roles in limb morphogenesis.

Apoptotic cell death in the developing limb of mouse fetuses was examined sequentially on days 11-15 of gestation by means of Nile blue (NB) sulfate staining with special reference to its relation to limb morphogenesis. With some exceptions, programmed cell death (PCD) in the hand and foot was observed in the mesenchyme but not in the surface ectoderm. We found that during digital formation PCD begins at the proximal portion of the interdigital mesenchyme and subsequently expands distally. Therefore, the initial PCD that occurs in the interdigital zones may determine the proximal ends of digital separation and also contribute to the demarcation between the palm (sole) and digits (toes). During digital separation, the areas of PCD in the interdigital zones were found to become larger and expand distally on day 13, which may be necessary for the separation of digits and for determining the interdigital area to disappear. PCD in presumptive phalangeal joints was also found to proceed from proximal to more distal joints. The PCD in presumptive joints may be required for the separation of phalanges and metacarpal (metatarsal) bones and for the formation of joint cavities. In addition, intense PCD was observed in the radial (tibial) and ulnar (fibular) margins of the hand and foot plates for 4-5 days. Such PCD at marginal areas seems to prevent the formation of supernumerary digits (preaxial and postaxial polydactyly) and other digital malformations. Therefore, the timing when PCD commences and ends, the sites where PCD occurs, and the intensity, duration, and proximo-distal progress of PCD appear to be genetically determined, and the elimination of unnecessary cells by PCD may be essential for normal limb morphogenesis. The present findings also suggest that the normal progress of PCD in the hand and foot plates of rodent fetuses may prevent the formation of some limb malformations such as webbing fusion of digits, polydactyly, or cleft hand/foot.

Animals↗
PubMed1998

Influence of epidermal growth factor and transforming growth factor beta-1 on patterns of fetal mouse lung branching morphogenesis in organ culture.

Transforming growth factor-beta (TGF-beta), a potent inhibitor of epithelial cell proliferation, and epidermal growth factor (EGF), a mitogenic polypeptide that binds to cell surface receptors, are important regulators of cell differentiation; however, their distinct role(s) in lung development and their mechanisms of action are not well understood. We evaluated the effects of these factors on lung morphogenesis in murine fetal lungs at gestational day 14 (time:zero) and again after 7 days in culture. Baseline controls were cultured after tracheal transection in supplemented BGJb medium, and other tracheally transected lungs were cultured following addition of EGF (10 ng/ml BGJb), TGF-beta1 (2 ng/ml BFJb), or with both in combination added to the medium. The control lungs in culture had poorly developed airways and an absence of defined acinar structures. The addition of EGF resulted in hyperplasia of primary airways with stunted outgrowths, monopodial branching, and absence of distinct acinar structures. Addition of TGF-beta1 alone, led to significant elongation of primary airways, without normal airway branching; however, terminal dipodial branching was seen and the prospective pulmonary acini were well defined. Combination of these growth factors (GF) resulted in a more normal branching pattern and differentiation, suggesting their epigenetic role in lung morphogenesis and mutual interactive mechanisms that regulate lung development. These lungs had more abundant and larger lamellar bodies than those after other treatments. Control lungs remained immature with prominent glycogen aggregates with occasional dense lamellar bodies. The total protein and DNA contents were highest with EGF treatment, followed by combination treatment; these observations were supported by immunohistochemical localization of proliferating cell nuclear antigen, an indication of the proliferative state of tissues. All the surfactant proteins were relatively unaltered and their messages were up-regulated for SP-A, but down-regulated for SP-B and SP-C in the lungs treated with growth factors. In conclusion, we have demonstrated enhanced biochemical and structural development of lungs treated in vitro with GF, and propose that further research in this area may lead to therapeutic uses of GF alone or in combination with other agents for the treatment of newborn respiratory distress due to lung immaturity or hypoplastic lung development.

Animals↗
PubMed1998

Common role for each of the cGATA-4/5/6 genes in the regulation of cardiac morphogenesis.

The GATA-4/5/6 genes encode transcription factors implicated previously in the regulation of cardiac-specific differentiation programs. However, recent analyses of mouse GATA-4 null mutations found evidence for function in endoderm development (in vitro) and embryonic morphogenesis (in vivo). Whether each of the three cardiac-associated GATA factors function within distinct or common developmental programs was previously untested; past studies defined specific and distinct roles for each of the GATA-1/2/3 genes in embryonic hematopoiesis. In this study, we compare the transcript patterns of cGATA-4/5/6 during chick embryogenesis. Each of the three GATA factors is expressed in a similar pattern within gastrulating cells of the primitive streak, prior to determination of the cardiomyocyte progenitors, and later within the lateral plate mesoderm and associated endoderm layer. The patterns overlap but extend beyond the presumptive cardiomyocyte population expressing cNkx-2.5. Later in development, cGATA-4/5/6 are all transcribed throughout the differentiating heart, in similar but not identical patterns, within the endocardium, myocardium, and great vessels. In order to test the function of GATA factors during chick cardiogenesis, embryos were cultured in vitro in the presence of antisense oligomers designed to deplete specifically transcripts encoding cGATA-4/5/6, beginning around stage 7. When oligomers are used to target transcripts for all three genes, a high percentage of the embryos develop abnormal hearts related to the failure to form a normal primitive heart tube. In the most severe phenotype, cardiac bifida results in two bilateral beating hearts. In some embryos, the paired heart primordia undergo partial fusion but fail to form a single looping heart tube. In all cases, cellular differentiation is not obviously affected, as the abnormal hearts form beating tissue. Depletion of transcripts encoding any single GATA factor, or any combination of two GATA factors, does not affect development. The partial depletion of all three genes in chick results in a remarkably similar phenotype compared to the null GATA-4 mutation in mouse. Therefore, in the chick, each of the GATA-4/5/6 genes functions in a common pathway, at the time of cardiac crescent formation, for regulating early embryonic cardiac morphogenesis, apparently associated with embryonic folding or the migration of primordia to form a primitive tube.

Animals↗
PubMed2001

Postnatal mammary gland morphogenesis.

Mammary glands develop postnatally by branching morphogenesis creating an arborated ductal system on which secretory lobuloalveoli develop at pregnancy. This review focuses on the interrelated questions of how ductal and alveolar morphogenesis and growth are regulated in the mouse mammary gland and covers progress made over approximately the last decade. After a brief overview of glandular development, advances in understanding basic structural questions concerning mechanisms of duct assembly, elongation, and bifurcation are considered. Turning to growth regulation, remarkable progress has taken place based largely on the study of genetically engineered mice that lack or overexpress a single gene. The use of mammary glands from these and wildtype animals in sophisticated epithelial-stromal or epithelial-epithelial recombination experiments are reviewed and demonstrate paracrine mechanisms of action for the classical endocrine mammogens, estrogen, progesterone, growth hormone, and prolactin. In addition, IGF-1, EGF, or related peptides, and elements of the activin/inhibin family, were shown to be necessary for ductal growth. The inhibition of ductal growth, and in particular, lateral branching, is necessary to preserve stromal space for later lobuloalveolar development. Excellent evidence that TGF-beta1 naturally inhibits this infilling, possibly by blocking hepatocyte growth factor synthesis, is reviewed along with evidence indicating that the action of TGF-beta1 is modulated by its association with the extracellular matrix. Finally, experimental approaches that may help integrate the wealth of new findings are discussed.

Animals↗