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H Schorle

Publications and source records attributed to H Schorle.

16 recordsLinked to original sources
PubMed2006

Normal embryonic development and cardiac morphogenesis in mice with Wnt1-Cre-mediated deletion of connexin43.

Mice harboring a null mutation in the gap junction protein connexin43 (Cx43) die shortly after birth due to an obstruction of the right ventricular outflow tract of the heart. These hearts exhibit prominent pouches at the base of the pulmonary outlet, i.e., morphological abnormalities that were ascribed to Cx43-deficiency in neural crest cells. In order to examine the Cx43 expression pattern in neural crest cells and derived tissues and to test whether neural crest-specific deletion of Cx43 leads to the conotruncal defects seen in Cx43null mice, we ablated Cx43 using a Wnt1-Cre transgene. Deletion of Cx43 was complete and occurred in neural crest cells as well as in neural crest-derived tissues. Nevertheless, hearts of mice lacking Cx43 specifically in neural crest cells were indistinguishable from controls. Thus, the morphological heart abnormalities of Cx43 null mice are most likely not caused by lack of Cx43 in neural crest cells.

Animals↗
PubMed2006

Diagnostic value of markers M2A, OCT3/4, AP-2gamma, PLAP and c-KIT in the detection of extragonadal seminomas.

AIMS: To compare the suitability of new seminoma markers including transcription factors AP-2gamma, OCT3/4 and M2A for detection of metastatic and extragonadal seminomas with the two well-known markers c-KIT and PLAP. MATERIALS AND METHODS: The immunohistochemical distribution of PLAP, c-KIT, M2A, AP-2gamma and OCT3/4 was examined in two pineal germinomas, 28 metastatic seminomas and 10 of their testicular primaries. Evaluation of specificity was achieved by additional tissue array studies on 75 malignancies other than germ cell tumours (GCT). Clinical data including serum PLAP were available in 18 patients. RESULTS: Compared with other markers, significantly better staining results were observed with antibodies to M2A and AP-2gamma in all seminomatous GCT. In contrast, the staining pattern with antibodies to c-KIT, PLAP and OCT3/4 was variable or absent. The lowest specificity was obtained with c-KIT, which was expressed in a variety of non-GCT. The only M2A+ mesothelioma expressed no other seminoma markers. No correlation between serum PLAP level and tissue PLAP expression was found. CONCLUSIONS: M2A and AP-2gamma are the most sensitive markers for seminoma metastases or primary extragonadal seminomas. Combination of these markers provides highly specific and clear results for detection of a seminomatous GCT.

Adult↗
PubMed2001

Mice overexpressing genes from the 22q11 region deleted in velo-cardio-facial syndrome/DiGeorge syndrome have middle and inner ear defects.

Velo-cardio-facial syndrome/DiGeorge syndrome (VCFS/DGS) is a congenital anomaly disorder associated with hemizygous 22q11 deletions. We previously showed that bacterial artificial chromosome (BAC) transgenic mice overexpressing four transgenes, PNUTL1, (CDCrel-1), GP1B beta, TBX1 and WDR14, had reduced viability, cardiovascular malformations and thymus gland hypoplasia. Since these are hallmark features of VCFS/DGS, we analyzed the mice for additional anomalies. We found that the mice have important defects in the middle and inner ear that are directly relevant to the disorder. The most striking defect was the presence of chronic otitis media, a common finding in VCFS/DGS patients. In addition, the mice had a hyperactive circling behavior and sensorineural hearing loss. This was associated with middle and inner ear malformations, analogous to Mondini dysplasia in humans reported to occur in VCFS/DGS patients. We propose that overexpression of one or more of the transgenes is responsible for the etiology of the ear defects in the mice. Based upon its pattern of expression in the ear and functional studies of the gene, TbX1 likely plays a central role. Haploinsufficiency of TBX1 may be responsible for ear disorders in VCFS/DGS patients.

Abnormalities, Multiple↗
PubMed2001

TBX1 is responsible for cardiovascular defects in velo-cardio-facial/DiGeorge syndrome.

Velo-cardio-facial syndrome (VCFS)/DiGeorge syndrome (DGS) is a human disorder characterized by a number of phenotypic features including cardiovascular defects. Most VCFS/DGS patients are hemizygous for a 1.5-3.0 Mb region of 22q11. To investigate the etiology of this disorder, we used a cre-loxP strategy to generate mice that are hemizygous for a 1.5 Mb deletion corresponding to that on 22q11. These mice exhibit significant perinatal lethality and have conotruncal and parathyroid defects. The conotruncal defects can be partially rescued by a human BAC containing the TBX1 gene. Mice heterozygous for a null mutation in Tbx1 develop conotruncal defects. These results together with the expression patterns of Tbx1 suggest a major role for this gene in the molecular etiology of VCFS/DGS.

Animals↗
PubMed2000

Regulatory roles of AP-2 transcription factors in vertebrate development, apoptosis and cell-cycle control.

AP-2 transcription factors represent a family of three closely related and evolutionarily conserved sequence-specific DNA-binding proteins, AP-2alpha, -beta and -gamma. Subsequent studies have identified spatially and temporally regulated embryonic expression patterns in a number of different tissues including neural crest derivatives, neural, epidermal and urogenital tissues. Here, we review the current understanding of developmental defects in AP-2-deficient mice and consider regulatory functions of AP-2 in control of apoptosis, cell cycle, and gene expression. Recently, the first inherited human disorder, Char syndrome, was identified to be caused by AP-2beta missense mutations. In light of the manifold and essential functions of AP-2 proteins in cell growth, differentiation and programmed death, mutations or changes in precisely programmed expression patterns are likely to contribute to other congenital malformations or neoplastic diseases.

Animals↗
PubMed2000

Expression of Cdcrel-1 (Pnutl1), a gene frequently deleted in velo-cardio-facial syndrome/DiGeorge syndrome.

The murine Cdcrel-1 (Pnutl1) gene belongs to the family of septins, which are thought to be involved in cytokinesis in yeast, Drosophila and vertebrates. Recent studies implicate Cdcrel-1 in the regulation of vesicle transport in neurons of the adult brain. The human homologue, hCDCREL-1 maps to chromosome 22q11.2, a region commonly deleted in patients displaying velo-cardio-facial syndrome (VCFS) or DiGeorge syndrome (DGS). During development, Cdcrel-1 transcripts are expressed from E10.5 on in the nervous system such as the dorsal root ganglia and the cranial ganglia as well as the lateral layer of the neural tube, the area where terminally differentiated neurons are located. Low level expression is found in the mesenchyme of the frontonasal mass and the limb bud mesenchyme of E11.5 and E13.5 murine embryos. At E15.5, expression is detected in the nervous tissue and in the neural layer of the eye. Based on the expression pattern as well as clinical data, Cdcrel-1 may be involved in the etiology of VCFS/DGS.

Animals↗
PubMed1999

Spatiotemporal expression pattern of keratins in skin of AP-2alpha-deficient mice.

Transcription factor AP-2alpha has been implicated as being a cell-type-specific regulator of gene expression during vertebrate embryogenesis based on its expression pattern in neural crest cells, ectoderm, and the nervous system in mouse and frog embryos. In mice, AP-2alpha is expressed in surface ectoderm beginning at the single cell layer state around E8.75. AP-2alpha-deficient mice, derived by targeted mutagenesis, display a severe ventral closure defect resulting in cranio-abdominoschisis and a hypoplasia of the cranial ganglia. This study analyzed the effect of a targeted disruption of the AP-2alpha gene on the architecture and the expression of intermediate filaments in skin. We analyzed skin samples from newborn mice and found no difference in either the morphology of the skin or the amount of intermediate filaments expressed. This suggests that despite the results from other analyses, loss of transcription factor AP-2alpha does not affect the expression of intermediate filaments in the skin of newborn animals. We found an altered spatial distribution of intermediate filament expression in the single layered cranial ectoderm during days 9-12 of gestation leading to an evenly distributed expression of keratin 5 and 15 in the mutants. Furthermore, the mutants lack a ring of ectodermal cells highly positive for keratin 15 in the area where lens induction occurs, indicating a defect in the inductive interactions underlying eye formation.

Animals↗
PubMed1996

Transcription factor AP-2 essential for cranial closure and craniofacial development.

During closure of the neural tube in the mouse, transcription factor AP-2 is expressed in ectoderm and in neural-crest cells migrating from the cranial neural folds. Cranial neural crest cells provide patterning information for craniofacial morphogenesis, generate most of the skull bones, and together with placodal ectoderm, form the cranial ganglia. To study the role of AP-2 during embryogenesis, we undertook a targeted mutagenesis of the AP-2 gene in the mouse. Here we report that AP-2(-/-) mice died perinatally with cranio-abdominoschisis and severe dismorphogenesis of the face, skull, sensory organs and cranial ganglia. Failure of cranial closure between 9 and 9.5 days postcoitum coincided with increased apoptosis in the midbrain, anterior hindbrain and proximal mesenchyme of the first branchial arch, but did not involve loss of expression of twist or Pax-3, two other regulatory genes known to be required for cranial closure.

Animals↗
PubMed1996

[Generalized autoimmune diseases in BALB/c mice with a genetically dependent interleukin-2 deficiency].

Il-2 has been described as a key cytokine regulating the growth, differentiation and function of lymphocytes. To better understand its in vivo function Il-2 deficient mouse mutants were generated on a mixed (129/Ola x C57BL6) genetic background which predominantly develop an ulcerative colitis-like disease (10). To further elucidate the complex disease syndrome of Il-2-/-mice and to study the possible contribution of genetic factors in its pathogenesis we have bred the IL-2-/-mice to various genetic backgrounds. The resulting phenotypes were analyzed clinically and morphologically and the status of their immune system was assessed. Il-2-/-mice backcrossed to BALB/c genetic background develop a generalized autoimmune disease, which becomes manifest as hemolytic anemia, follicular hyperplasia of lymphoid organs, inflammatory changes of pancreas, liver, heart, lungs and thoracal blood vessels but not of the colon (11). The mutants all die within 5 weeks of age. The changes of the immune system are dominated by an uncontrolled polyclonal activation and proliferation of T and B cells, associated with an increased production of autoantibodies. Treatment of Il-2-/-Balb/c mice with anti-gp39 (CD40L) antibody inhibited activation of B cells and CD8+ T cells, however, it did not affect the activation of CD4+ T cells. In such treated mice amelioration of hemolytic anemia but not of inflammatory lesions in most of the affected organs could be recognized. The primary immunologic change of Il-2-/-mice is obviously an uncontrolled proliferation of CD4+ T cells. It suggests that the in vivo function of IL-2 which is not compensated by other cytokines is the maintenance of self tolerance.

Animals↗
PubMed1995

Generalized autoimmune disease in interleukin-2-deficient mice is triggered by an uncontrolled activation and proliferation of CD4+ T cells.

Interleukin-2-deficient mice (IL-2-/-) crossed to a BALB/c genetic background develop a lymphoproliferative syndrome with severe hemolytic anemia and die within 5 weeks of age. The presence of autoantibodies of various specificities and inflammatory lesions in several organs are indicative of a generalized auto-immune disease. No alterations of the immune system were observed in 6-day-old animals, but 10-day-old mice already showed an increased proliferation and polyclonal activation of lymphocytes. The treatment of IL-2-/- mice with anti-gp39(CD40L) antibody prevented the disease and indicated that the appearance of activated CD4- T cells (CD44high, CD69-) represents the first alteration of the immune system in IL-2-/- mice. Collectively, our results suggest that an essential role of IL-2 in vivo, which is not compensated by other cytokines, is the maintenance of self tolerance.

Anemia, Hemolytic, Autoimmune↗
PubMed1995

Antiviral immune responses in mice deficient for both interleukin-2 and interleukin-4.

Antiviral immune responses of mice lacking interleukin-2 (IL-2) or IL-4 or both IL-2 and IL-4 (IL-2/4) were compared by using different viruses. Primary cytotoxic T-lymphocyte (CTL) responses against lymphocytic choriomeningitis virus (LCMV) were only moderately reduced in mice lacking IL-2 and were normal in mice lacking IL-4. Mice deficient in both interleukins exhibited variable and more strongly reduced but nevertheless in vivo protective LCMV-specific CTL responses. Similar results were obtained with vaccinia virus. Upon virus-specific restimulation in vitro, spleen cells from IL-2- and IL-2/4-deficient mice failed to generate CTL responses against virus-infected target cells, whereas the response of mice deficient in only IL-4 was comparable to that of control mice. The addition of IL-2 during in vitro restimulation completely restored the responses of both IL-2 and IL-2/4-deficient mice. T-helper-cell-independent immunoglobulin M and T-helper-cell-dependent immunoglobulin G antibody responses against vesicular stomatitis virus glycoprotein were within normal ranges for the various mutant mice. After LCMV infection, specific antibody responses against LCMV nucleoprotein were reduced four- to eightfold. These results show that mice lacking IL-2/4 have an overall tendency to exhibit more severely reduced CTL responses than IL-2- or IL-4-deficient mice. Nevertheless, and surprisingly, in vivo protective immune responses were mounted in the absence of IL-2/4, suggesting that besides a minor contribution from IL-4, other interleukins compensate in vivo for the lack of IL-2 in IL-2-deficient mice.

Animals↗
PubMed1994

Development and proliferation of lymphocytes in mice deficient for both interleukins-2 and -4.

Interleukin (IL)-2 and IL-4 are considered as important regulators of growth and differentiation of lymphocytes. We report that in mice made deficient for both IL-2 and IL-4 by gene targeting all major T cell subsets and B cells were normal, indicating that IL-2 and IL-4 are not essential for development of the immune system. Paradoxically, proliferation of T cells was increased in both IL-2 and IL-4-deficient homozygous mice.

Animals↗
PubMed1993

Immune responses in interleukin-2-deficient mice.

The role of costimulatory signals in T cell induction was evaluated in mice lacking the interleukin-2 (IL-2) gene. In vitro secondary antiviral T cell responses were absent unless IL-2 was added, confirming the crucial role of IL-2 in vitro. In vivo, primary and secondary cytotoxic T cell responses against vaccinia and lymphocytic choriomeningitis virus were within normal ranges. B cell reactivity to vesicular stomatitis virus was not impaired. T helper cell responses were delayed but biologically functional. Natural killer cell activity was markedly reduced but inducible. These normal in vivo immune responses in IL-2-deficient mice question the importance of IL-2 as defined by in vitro studies.

Animals↗
PubMed1993

Ulcerative colitis-like disease in mice with a disrupted interleukin-2 gene.

Mice deficient for interleukin-2 develop normally during the first 3-4 weeks of age. However, later on they become severely compromised, and about 50% of the animals die between 4 and 9 weeks after birth. Of the remaining mice, 100% develop an inflammatory bowel disease with striking clinical and histological similarity to ulcerative colitis in humans. The alterations of the immune system are characterized by a high number of activated T and B cells, elevated immunoglobulin secretion, anti-colon antibodies, and aberrant expression of class II major histocompatibility complex molecules. The data provide evidence for a primary role of the immune system in the etiology of ulcerative colitis and strongly suggest that the disease results from an abnormal immune response to a normal antigenic stimulus.

Aging↗
PubMed1991

Development and function of T cells in mice rendered interleukin-2 deficient by gene targeting.

Interleukin-2 (IL-2) is a lymphocytotropic hormone which is thought to have a key role in the immune response of mammalian cells. It is produced by a subpopulation of activated T-lymphocytes and acts in vitro as the principal auto- and paracrine T-cell growth factor (for reviews see refs 1-3). IL-2 is, however, not the sole T-cell growth factor, nor does it act exclusively on T cells, also promoting growth of NK cells and differentiation of B cells. A role for IL-2 in T-cell development has been postulated but remains controversial. Here we test the requirement for IL-2 in vivo using IL-2-deficient mice generated by targeted recombination. We find that mice homozygous for the IL-2 gene mutation are normal with regard to thymocyte and peripheral T-cell subset composition, but that a dysregulation of the immune system is manifested by reduced polyclonal in vitro T-cell responses and by dramatic changes in the isotype levels of serum immunoglobulins.

Animals↗