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PubMed2001

The hedgehog pathway and basal cell carcinomas.

Developmental pathways first elucidated by genetic studies in the fruit fly, Drosophila melanogaster, are conserved in vertebrates, and disruption of these pathways has been associated with various human congenital anomalies. Many developmental genes continue to play an important role in regulation of cell growth and differentiation after embryogenesis, and mutations in some of these genes can result in cancer. Basal cell carcinoma (BCC) of the skin is the most common type of cancer in humans. Although most BCCs are sporadic, in rare cases, individuals have a hereditary disease, Gorlin syndrome, that predisposes to multiple skin tumors as well as a variety of birth defects. Mutations in the human homolog of a Drosophila gene, patched, underlie Gorlin syndrome. Genetic studies in Drosophila show that patched is part of the hedgehog signaling pathway, important in determining embryonic patterning and cell fate in multiple structures of the developing embryo. Human patched is mutated in sporadic as well as hereditary BCCs, and inactivation of this gene is probably a necessary if not sufficient step for tumor formation. Delineation of the biochemical pathway in which patched functions may lead to rational medical therapy for skin cancer and possibly other tumors.

Animals↗
PubMed1997

The supplementation of culture medium with protease improves the hatching rate of mouse embryos.

Mammalian embryos are known to exhibit delayed development and have lower hatching rates in vitro than in vivo because of inadequate culture condition. These discrepancies may be due to a deficiency of the paracrine factors and proteolytic enzymes which exist in the oviduct and uterus. In order to evaluate the effects of proteases on embryonic development and hatching, 2-cell mouse embryos were cultured for 72 h with or without proteases. The addition of 1.0 microg/ml pronase (PE) and/or 0.1 microg/ml proteinase K (PK) did not affect embryonic development up to the blastocyst stage (94.1% versus 88.2%; 92.2% versus 90.2%, respectively) but significantly increased the hatching rate (60.4% versus 39.2%, 71.8% versus 35.3%, respectively). However, the addition of alpha-chymotrypsin (Chymo) was detrimental to embryonic development and hatching. Changes in the structure of the zona pellucida (ZP) structure of embryos which had been cultured in human tubal fluid (HTF) medium with PE and PK were assessed by fluorescein isothiocyanate-conjugated (FITC)-casein. Embryos cultured in HTF-PE and PK were not stained with FITC-casein. When these embryos were cultured within oviducts, their perivitelline space (PVS) became strongly stained with FITC-casein which was easily removed by phosphate-buffered saline washing. This suggests that PE and PK altered the structure of the ZP. We suggest that the addition of PE and PK to culture media may accelerate the hatching of embryo, by structurally altering the ZP and PVS. This may provide a valuable and effective assisted hatching technique for human in-vitro fertilization-embryo transfer.

Animals↗
PubMed1997

Developmental genes and cancer: role of patched in basal cell carcinoma of the skin.

Many genes originally identified because of their role in embryonic development are also important in postnatal control of cell growth and differentiation. Mutations in some of these genes have been shown to cause cancer. Basal cell carcinoma (BCC) of the skin is the most common cancer in humans. More than 750000 new cases are diagnosed annually, and the incidence is rising. BCCs are slow-growing, locally invasive tumors that rarely metastasize but can result in extensive morbidity through local recurrence and tissue destruction. Epidemiologic studies suggest that sunlight (particularly UVB radiation) is a strong risk factor for BCC formation, although other factors are also involved. The nevoid basal cell carcinoma syndrome (NBCCS), a rare genetic disorder, is characterized by predisposition to BCCs and other tumors as well as to a wide range of developmental defects. NBCCS maps to chromosome 9q22.3, and loss of heterozygosity at this site in both sporadic and hereditary BCCs suggests that it functions as a tumor suppressor. The gene for NBCCS was recently cloned and is the human homologue of the Drosophila gene "patched." Genetic studies in Drosophila show that patched is part of the hedgehog signaling pathway, which is important in determining embryonic patterning and cell fate in multiple structures of the developing embryo. Human patched is mutated in both hereditary and sporadic BCCs, and inactivation of this gene is probably a necessary, if not sufficient, step for BCC formation. Delineation of the biochemical pathway in which patched functions may lead to rational medical therapy for BCCs and possibly for other tumors associated with NBCCS.

Animals↗
PubMed1996

Intracytoplasmic sperm injection for Rhesus monkey fertilization results in unusual chromatin, cytoskeletal, and membrane events, but eventually leads to pronuclear development and sperm aster assembly.

The disassembly and reorganization of sperm-derived structures are landmarks for the onset of embryonic development. Since complete information on these events is not yet available, we examined the disassembly of the sperm axoneme, the formation of the sperm aster, and the decondensation and development of the male and female pronuclei in inseminated Rhesus monkey oocytes conceived by in-vitro fertilization (IVF) or by intracytoplasmic sperm injection. During IVF, the spermatozoa lose their acrosomes after contacting the zona pellucida, and the plasma membrane and nuclear envelope disappear after fusion with the oolemma. Subsequently, a sperm aster of microtubules forms around the proximal centriole, which is bound to the sperm connecting piece. This process is then followed by the formation of both pronuclei, which single sperm centriole later duplicates and the bipolar mitotic apparatus is observed. Following sperm injection, the spermatozoa have both an intact plasma membrane and acrosome. Although the microtubules form the sperm aster in a fashion identical to that seen during IVF, the presence of an intact acrosome appears to be associated with a heterogeneity in the decondensation of sperm chromatin. While this may indicate an abnormal pattern of chromatin decondensation during the formation of the male pronucleus following sperm injection, the male pronucleus eventually fully decondenses, as during IVF. Sperm mitochondria are displaced as the sperm centriole is exposed. Annulate lamellae and a previously undescribed organelle which seems to contain annulate lamellae precursors, as well as maternal mitochondria, are found in association with the developing pronuclear envelopes. This information increases understanding of fertilization in primates, and may also be of significance for use in assisted human reproduction as well as in the preservation of endangered mammalian species. In addition, these results demonstrates the similarities between fertilization in Rhesus monkeys and humans, providing additional evidence for the use of this non-human primate as a model system in which to investigate the cellular and molecular biological basis of human reproduction.

Animals↗
PubMedDate not supplied

Ultrastructural studies of the nucleoli in diploid and trisomic chickens.

Chickens having a trisomic complement for the nucleolar organizer region (NOR) serve as a model for investigations on gene expression, molecular regulation, and physiological alterations resulting from extra genetic material. Of fundamental importance is the question of whether the extra set of ribosomal cistrons in trisomic chickens generates a morphologically and biochemically complete nucleolus. Ultrastructural and cytochemical studies of diploid and trisomic embryonic and adult cells were undertaken. All structures identified in trisomic cells as nucleoli by gross morphology were shown to be RNA rich by acridine orange fluorescence. At the ultrastructural level, the expected granular and fibrillar components were identified in all nucleoli of trisomic cells. Fibrillar centers, indicative of NOR's, were seen in all cases. These and other results from silver staining suggest full gene activity for each of the three chromosomes in the trisomic cell at all stages of development.

Animals↗
PubMed2007

Telomere length in mammalian cells exposed to low- and high-LET radiations.

Telomeres are specialised nucleoprotein complexes that serve as protective caps of linear eukaryotic chromosomes. The loss of the ends of the chromosomes due to these un-rejoined double strand breaks (DSBs) may not be lethal to the cell, but may instead result in the loss of functional telomeres, chromosome fusions and initiation of breakage/fusion/bridge cycle-induced chromosome instability. The telomeres also participate in the process of DNA repair, as evidenced by 'de novo' synthesis of telomere repeats at DSBs and by the capacity of telomeres to binding the essential components of the DNA repair machinery. Based on the observation that high-LET radiations efficiently induce chromosome aberrations, it was tested whether protons were able to affect telomere structure. Human primary fibroblasts (HFFF2) and mouse embryonic fibroblasts (MEFs) were irradiated with 4 Gy of 3 MeV protons at the radiobiology facility of the INFN-LNL. Experiments with X rays were also carried out. Cells were fixed after either 24 h or 15 d from treatment. A difference in average telomere length, measured by quantitative fluorescence in situ hybridisation (Q-FISH), between X rays and protons treatment was observed. X rays are able to modify telomere length in HFFF2 harvested at a later time. On the other hand, 3 MeV low-energy protons induced, both in HFFF2 and in MEFs, a significant increase in telomere length at short as well as at long harvesting time periods from treatment. These results seem to indicate that lesions characterised by different complexity, as those expected after low-energy protons and those induced by damage similar to that induced by sparsely ionising radiation, are able to modulate telomere elongation at different time periods.

Animals↗
PubMed2004

VEGF is required for the maintenance of dorsal root ganglia blood vessels but not neurons during development.

Vascular endothelial growth factor (VEGF) is a potent regulator of vascular function through its control of multiple endothelial cell functions. In addition to its key role in vascularization, VEGF has recently been shown to have neurotrophic activity during hypoxic stress. In the central and peripheral motor nervous system, VEGF treatment increased neuronal vascularization and perfusion, as well as having direct trophic effects on neurons and Schwann cells. However, the role of VEGF in the sensory nervous system remains unclear. To characterize the differential effects of VEGF on endothelial cells and neurons in sensory ganglia, we used explanted mouse dorsal root ganglia (DRG), a culture system containing neurons and endothelial cells in close apposition. We show that VEGF is expressed by neurons and satellite cells, but not by endothelial cells or pericytes. On the other hand, the tyrosine kinase VEGF receptor VEGFR-2 was robustly expressed by endothelial cells throughout the extensive DRG capillary network, but not found at either the transcript or protein level in sensory neurons or other nonendothelial cells of the DRG. Both soluble receptor sequestration of VEGF and small molecule kinase inhibition of VEGFR-2 signaling rapidly disrupted the connectivity, branching, and structural integrity of the capillary network of embryonic DRG; this effect was no longer evident postnatally. However, VEGF inhibition showed no detectable effect on neuronal health at any stage analyzed. These data suggest that endogenous VEGF is a strict requirement for vascular, but not neuronal, maintenance in developing sensory ganglia.

Animals↗
PubMed1998

Autoantigen Ku in the brain. Developmentally regulated expression and subcellular localization.

A double-stranded DNA end-binding factor with high levels of expression in brain and testis of adult mice was identified as the Ku protein, earlier described as an autoantigen in connective tissue diseases and found to be essential for recombination of the immunoglobulin genes and DNA repair. High Ku levels were found in the cerebellum and pituitary gland, lower levels in the hippocampus, hypothalamus and white matter structures. Ku levels were much higher in embryonic rat brain than in the adult brain, suggesting a role of the Ku protein in brain development. In embryonic rat brain, Ku was associated with cell nuclei, but was predominantly located in the cytosol in the adult rat cerebellum and hippocampus. The abundant expression of Ku in the brain suggests the involvement of Ku autoantibodies in the pathogenesis of neuropsychiatric complications in connective tissue diseases.

Animals↗
PubMed1997

Molecular basis of the nevoid basal cell carcinoma syndrome.

Many genes originally identified because of their role in embryonic development are also important in control of cell growth and differentiation postnatally. Mutations in some of these genes have been shown to contribute to carcinogenesis. The nevoid basal cell carcinoma syndrome is an autosomal dominant disorder that predisposes to basal cell carcinomas of the skin as well as widespread developmental defects. The gene for this disorder, NBCCS, maps to chromosome 9q22.3, and loss of heterozygosity at this site in both sporadic and hereditary basal cell carcinomas suggests that it functions as a tumor suppressor. NBCCS was positionally cloned and shown to be the human homologue of the Drosophila gene, patched. Drosophila patched is part of the hedgehog signaling pathway, important in determining embryonic patterning and cell fate in multiple structures of the developing embryo. That mutations in human patched result in dysregulation of several genes known to play a role in both organogenesis and carcinogenesis may explain both the birth defects and the cancer predisposition seen in the nevoid basal cell carcinoma syndrome.

Animals↗
PubMed1990

The orthodenticle gene encodes a novel homeo domain protein involved in the development of the Drosophila nervous system and ocellar visual structures.

The orthodenticle (otd) locus of Drosophila is required for embryonic development, and null mutations of otd cause defects in head development and segmental patterning. We show here that otd is necessary for the formation of the embryonic central nervous system (CNS). otd mutations result in the formation of an abnormal neuropil and in the disappearance of identified neurons associated with the midline of the CNS. In addition, otd is allelic to ocelliless (oc), a mutation that causes the deletion of the ocelli of the adult fly. We have identified a transcription unit corresponding to the otd locus and find that it is expressed early in a stripe near the anterior pole of the cellular blastoderm and later in the region of the CNS from which these neurons normally arise. The predicted otd protein contains a well-conserved homeo domain and is therefore likely to be a transcriptional regulator involved in specifying cell fate both in the embryonic CNS and in the ocelli.

Alleles↗
PubMed2002

Differential role of bFGF and VEGF for vasculogenesis.

Primary vascular plexus originate from angioblasts through a process called vasculogenesis. The precise role of basic fibroblast growth factor (bFGF) and the vascular endothelial growth factor (VEGF) are both suggested as key regulators in vasculogenesis is still unclear. This crucial aspect was investigated by using time lapse observation of in vitro generated embryonic stem (ES) cell-derived endothelial structures which were recognizable by using the platelet cell adhesion molecule (PECAM-1) driven endothelial-specific expression of the live reporter gene enhanced green fluorescent protein (EGFP). In serum free conditions VEGF led to improved survival of angioblasts and to the formation of primitive endothelial tubes whereas bFGF alone increased their survival. Our study suggests that the complex process of vasculogenesis can be driven by VEGF alone but not by bFGF.

Cell Survival↗
PubMed1975

Transfer of iron-dextran across the placenta.

In pregnant mice. 55Fe-labeled iron-dextran (Imferon) is transferred across the placenta. It was detected in the bone marrow, liver, spleen and peripheral blood of the pregnant animal, as well as in the embryonic liver erythroid precursors and peripheral blood. Uptake by liver and peripheral blood cells of pregnant anemic mice and by liver erythroid precursors of anemic embryos was significantly higher than in normal control animals. Electron-microscopic examination revealed that the iron deposits in the embryonic liver erythroid precursors had the same structure as the injected Imferon.

Animals↗
PubMed2001

Comparison of two murine models of familial hypertrophic cardiomyopathy.

Although sarcomere protein gene mutations cause familial hypertrophic cardiomyopathy (FHC), individuals bearing a mutant cardiac myosin binding protein C (MyBP-C) gene usually have a better prognosis than individuals bearing beta-cardiac myosin heavy chain (MHC) gene mutations. Heterozygous mice bearing a cardiac MHC missense mutation (alphaMHC(403/+) or a cardiac MyBP-C mutation (MyBP-C(t/+)) were constructed as murine FHC models using homologous recombination in embryonic stem cells. We have compared cardiac structure and function of these mouse strains by several methods to further define mechanisms that determine the severity of FHC. Both strains demonstrated progressive left ventricular (LV) hypertrophy; however, by age 30 weeks, alphaMHC(403/+) mice demonstrated considerably more LV hypertrophy than MyBP-C(t/+) mice. In older heterozygous mice, hypertrophy continued to be more severe in the alphaMHC(403/+) mice than in the MyBP-C(t/+) mice. Consistent with this finding, hearts from 50-week-old alphaMHC(403/+) mice demonstrated increased expression of molecular markers of cardiac hypertrophy, but MyBP-C(t/+) hearts did not demonstrate expression of these molecular markers until the mice were >125 weeks old. Electrophysiological evaluation indicated that MyBP-C(t/+) mice are not as likely to have inducible ventricular tachycardia as alphaMHC(403/+) mice. In addition, cardiac function of alphaMHC(403/+) mice is significantly impaired before the development of LV hypertrophy, whereas cardiac function of MyBP-C(t/+) mice is not impaired even after the development of cardiac hypertrophy. Because these murine FHC models mimic their human counterparts, we propose that similar murine models will be useful for predicting the clinical consequences of other FHC-causing mutations. These data suggest that both electrophysiological and cardiac function studies may enable more definitive risk stratification in FHC patients.

Actins↗
PubMed2002

Whole-mount immunohistochemistry: a high-throughput screen for patterning defects in the mouse cerebellum.

Large-scale mouse mutagenesis experiments now under way require appropriate screening methods. An important class of potential mutants comprises those with defects in the development of normal cerebellar patterning. Cerebellar defects are likely to be identified often because they typically result in ataxia. Immunohistochemistry (IHC) is commonly used to reveal cerebellar organization. In particular, the antigen zebrin II (=aldolase C), expressed by stripes of Purkinje cells, has been valuable in revealing cerebellar pattern abnormalities. The development of whole-mount procedures in Drosophila, chick, and Xenopus embryos allows complex patterns to be studied in situ while preserving the integrity of the structure. By combining procedures originally designed for embryonic and early postnatal tissue analyses, we have developed a whole-mount IHC protocol using anti-zebrin II, which reveals the complex topography of Purkinje cells in the adult mouse cerebellum. Furthermore, the procedure is effective with a number of other antigens and works well on both perfusion-fixed and immersion-fixed tissue. By use of this approach, normal adult murine cerebellar topography and patterning defects caused by mutation can be studied without the need for three-dimensional reconstruction.

Animals↗
PubMed2006

Recruitment of new cells into the postnatal heart: potential modification of phenotype by periostin.

Establishment of the circulatory system occurs very early in development to support the rapid growth of the embryo. Therefore, the heart is the first functional organ to be formed during both avian and mammalian development. Historically, cardiac development has been considered to occur only during embryogenesis from cell sources located within the primordial structures that generate the myocardium and associated coronary vascular endothelium and smooth muscle and cardiac fibroblasts. Recently, however, contribution to the cardiac structures has been demonstrated to occur during embryonic development from extracardiac sources, like the anterior heart field, raising questions as to whether cardiogenesis may be an ongoing process that extends into adult life. In this brief article, we describe the contribution of circulating adult bone marrow hematopoietic stem cells to the cardiac cell populations and the potential regulation of their differentiation by the extracellular matrix protein, periostin.

Cell Adhesion Molecules↗
PubMed1989

Systematic elimination of parthenogenetic cells in mouse chimeras.

The developmental potential of primitive ectoderm cells lacking paternal chromosomes was investigated by examining the distribution of parthenogenetic cells in chimeras. Using GPI-1 allozymes as marker, parthenogenetic cells were detected in most organs and tissues in adult chimeras. However, these cells were under severe selective pressure compared with cells from normal fertilized embryos. In the majority of chimeras, parthenogenetic cells in individual animals were observed in a limited number of tissues and organs and, even in these instances, their contribution was substantially reduced. Nevertheless, parthenogenetic cells were detected more consistently in some organs, especially the brain, heart, kidney and spleen. In contrast, there was apparently a systematic selection against parthenogenetic cells in some tissues, most notably in skeletal muscle, liver and pancreas. These results suggest that paternally derived genes are probably required not only for the development of extraembryonic structures but also for subsequent development of embryonic tissues derived from the primitive ectoderm lineage.

Animals↗
PubMed2000

Role of apoptosis in the closure of neonatal ductus arteriosus.

Apoptosis regulates the remodeling of tissue during embryonic development by eliminating unwanted cells and structures. The present study investigated smooth muscle cell (SMC) proliferation and apoptosis in the neonatal ductus arteriosus (DA) during closure. In the DA of 39 swine neonates and 5 autopsy human neonates, apoptosis was detected using in situ end-labeling and electron microscopy, and proliferation was evaluated using proliferating cell nuclear antigen. In swine, apoptosis of SMC was first observed at 24h after birth. After 48h, both apoptosis and proliferation quickly increased and became most prominent at 3 days, mainly in the intima and inner media. From 5 days, both apoptosis and proliferation quickly disappeared, and were present to a minor extent at the 2 weeks after birth. During these processes, there was no sign of inflammation or necrosis. In humans, apoptosis was found in tissue specimens obtained from 2 term neonates who died at 1 and 5 days after birth. These findings suggest that SMC contribute to the functional closure of the DA by active constriction, and soon after, they switch to proliferation and apoptosis, which may contribute to the anatomical closure of the DA.

Animals↗
PubMed2004

Early myocardial function affects endocardial cushion development in zebrafish.

Function of the heart begins long before its formation is complete. Analyses in mouse and zebrafish have shown that myocardial function is not required for early steps of organogenesis, such as formation of the heart tube or chamber specification. However, whether myocardial function is required for later steps of cardiac development, such as endocardial cushion (EC) formation, has not been established. Recent technical advances and approaches have provided novel inroads toward the study of organogenesis, allowing us to examine the effects of both genetic and pharmacological perturbations of myocardial function on EC formation in zebrafish. To address whether myocardial function is required for EC formation, we examined silent heart (sih(-/-)) embryos, which lack a heartbeat due to mutation of cardiac troponin T (tnnt2), and observed that atrioventricular (AV) ECs do not form. Likewise, we determined that cushion formation is blocked in cardiofunk (cfk(-/-)) embryos, which exhibit cardiac dilation and no early blood flow. In order to further analyze the heart defects in cfk(-/-) embryos, we positionally cloned cfk and show that it encodes a novel sarcomeric actin expressed in the embryonic myocardium. The Cfk(s11) variant exhibits a change in a universally conserved residue (R177H). We show that in yeast this mutation negatively affects actin polymerization. Because the lack of cushion formation in sih- and cfk-mutant embryos could be due to reduced myocardial function and/or lack of blood flow, we approached this question pharmacologically and provide evidence that reduction in myocardial function is primarily responsible for the defect in cushion development. Our data demonstrate that early myocardial function is required for later steps of organogenesis and suggest that myocardial function, not endothelial shear stress, is the major epigenetic factor controlling late heart development. Based on these observations, we postulate that defects in cardiac morphogenesis may be secondary to mutations affecting early myocardial function, and that, in humans, mutations affecting embryonic myocardial function may be responsible for structural congenital heart disease.

Actins↗