15 research outputs found
Scatter Factor/Hepatocyte Growth Factor and Its Receptor, the c-met Tyrosine Kinase, Can Mediate a Signal Exchange between Mesenchyme and Epithelia during Mouse Development
Scatter factor/hepatocyte growth factor
(SF/HGF) has potent motogenic, mitogenic, and morphogenetic
activities on epithelial cells in vitro. The cell
surface receptor for this factor was recently identified:
it is the product of the c - m e t protooncogene, a
receptor-type tyrosine kinase. We report here the
novel and distinct expression patterns of SF/HGF and
its receptor during mouse development, which was determined
by a combination of in situ hybridization and
RNase protection experiments. Predominantly, we detect
transcripts of c - m e t in epithelial cells of various
developing organs, whereas the ligand is expressed in
distinct mesenchymal cells in close vicinity. In addition,
transient SF/HGF and c - m e t expression is found
at certain sites of muscle formation; transient expression
of the c - m e t gene is also detected in developing
motoneurons. SF/HGF and the c-met receptor might
thus play multiple developmental roles, most notably,
mediate a signal given by mesenchyme and received
by epithelial. Mesenchymal signals are known to govern
differentiation and morphogenesis of many epithelia,
but the molecular nature of the signals has remained
poorly understood. Therefore, the known
biological activities of SF/HGF in vitro and the embryonal
expression pattern reported here indicate that
this mesenchymal factor can transmit morphogenetic
signals in epithelial development and suggest a molecular
mechanism for mesenchymal epithelial interactions
Placental Failure in Mice Lacking the Mammalian Homolog of Glial Cells Missing, GCMa
The GCM family of transcription factors consists of Drosophila melanogaster GCM, an important regulator
of gliogenesis in the fly, and its two mammalian homologs, GCMa and GCMb. To clarify the function of these
mammalian homologs, we deleted GCMa in mice. Genetic ablation of murine GCMa (mGCMa) is embryonic
lethal, with mice dying between 9.5 and 10 days postcoitum. At the time of death, no abnormalities were
apparent in the embryo proper. Nervous system development, in particular, was not impaired, as might have
been expected in analogy to Drosophila GCM. Instead, placental failure was the cause of death. In agreement
with the selective expression of mGCMa in labyrinthine trophoblasts, mutant placentas did not develop a
functional labyrinth layer, which is necessary for nutrient and gas exchange between maternal and fetal blood.
Only a few fetal blood vessels entered the placenta, and these failed to thrive and branch normally. Labyrinthine
trophoblasts did not differentiate. All other layers of the placenta, including spongiotrophoblast and
giant cell layer, formed normally. Our results indicate that mGCMa plays a critical role in trophoblast
differentiation and the signal transduction processes required for normal vascularization of the placent
Placental Failure in Mice Lacking the Mammalian Homolog of Glial Cells Missing, GCMa
The GCM family of transcription factors consists of Drosophila melanogaster GCM, an important regulator
of gliogenesis in the fly, and its two mammalian homologs, GCMa and GCMb. To clarify the function of these
mammalian homologs, we deleted GCMa in mice. Genetic ablation of murine GCMa (mGCMa) is embryonic
lethal, with mice dying between 9.5 and 10 days postcoitum. At the time of death, no abnormalities were
apparent in the embryo proper. Nervous system development, in particular, was not impaired, as might have
been expected in analogy to Drosophila GCM. Instead, placental failure was the cause of death. In agreement
with the selective expression of mGCMa in labyrinthine trophoblasts, mutant placentas did not develop a
functional labyrinth layer, which is necessary for nutrient and gas exchange between maternal and fetal blood.
Only a few fetal blood vessels entered the placenta, and these failed to thrive and branch normally. Labyrinthine
trophoblasts did not differentiate. All other layers of the placenta, including spongiotrophoblast and
giant cell layer, formed normally. Our results indicate that mGCMa plays a critical role in trophoblast
differentiation and the signal transduction processes required for normal vascularization of the placent
Scatter Factor/Hepatocyte Growth Factor and Its Receptor, the c-met Tyrosine Kinase, Can Mediate a Signal Exchange between Mesenchyme and Epithelia during Mouse Development
Scatter factor/hepatocyte growth factor
(SF/HGF) has potent motogenic, mitogenic, and morphogenetic
activities on epithelial cells in vitro. The cell
surface receptor for this factor was recently identified:
it is the product of the c - m e t protooncogene, a
receptor-type tyrosine kinase. We report here the
novel and distinct expression patterns of SF/HGF and
its receptor during mouse development, which was determined
by a combination of in situ hybridization and
RNase protection experiments. Predominantly, we detect
transcripts of c - m e t in epithelial cells of various
developing organs, whereas the ligand is expressed in
distinct mesenchymal cells in close vicinity. In addition,
transient SF/HGF and c - m e t expression is found
at certain sites of muscle formation; transient expression
of the c - m e t gene is also detected in developing
motoneurons. SF/HGF and the c-met receptor might
thus play multiple developmental roles, most notably,
mediate a signal given by mesenchyme and received
by epithelial. Mesenchymal signals are known to govern
differentiation and morphogenesis of many epithelia,
but the molecular nature of the signals has remained
poorly understood. Therefore, the known
biological activities of SF/HGF in vitro and the embryonal
expression pattern reported here indicate that
this mesenchymal factor can transmit morphogenetic
signals in epithelial development and suggest a molecular
mechanism for mesenchymal epithelial interactions
The c-ros tvrosine kinase receptor I controls regionalization and differehiation of epithelial cells in the epididymis
The c-ros gene was originally identified in mutant form as an oncogene. The proto-oncogene encodes a
tyrosine kinase receptor that is expressed in a small number of epithelial cell types, including those of the
epididymis. Targeted mutations of c-ros in the mouse reveal an essential role of the gene in male fertility.
Male c-ros -1- animals do not reproduce, whereas the fertility of female animals is not affected. We
demonstrate that c-ros is not required in a cell autonomous manner for male germ cell development or
function. The gene, therefore, does not affect sperm generation or function in a direct manner. The primary
defect in the mutant animals was located in the epididymis, showing that c-ros controls appropriate
development of the epithelia, particularly regionalization and terminal differentiation. The epididymal defect
does not interfere with production or storage of sperm but, rather, with sperm maturation and the ability of
sperm to fertilize in vivo. Interestingly, sperm isolated from c-ros - / - animals can fertilize in vitro. Our
results highlight the essential role of the epididymis in male fertility and demonstrate a highly specific
function of the c-ros receptor tyrosine kinase during development of distinct epithelial cell
The extracellular-matrix protein matrilin 2 participates in peripheral nerve regeneration
Matrilins are adaptor proteins of the extracellular matrix
involved in the formation of both collagen-dependent and
collagen-independent filamentous networks. Although their
molecular structure and binding partners have been
characterized, the functional roles of the four matrilin family
members in vivo are still largely unknown. Here, we show that
matrilin 2, expressed in pre-myelinating Schwann cells during
normal development, profoundly influences the behaviour of
glial cells and neurons in vitro. When offered as a uniform
substrate, matrilin 2 increased neurite outgrowth of dorsal root
ganglia (DRG) neurons and enhanced the migration of both cell
line- and embryonic DRG-derived Schwann cells. Vice versa,
axonal outgrowth and cell migration were decreased in DRG
cultures prepared from matrilin-2-deficient mice compared with
wild-type (wt) cultures. In stripe assays, matrilin 2 alone was
sufficient to guide axonal growth and, interestingly, axons
favoured the combination of matrilin 2 and laminin over
laminin alone. In vivo, matrilin 2 was strongly upregulated in
injured peripheral nerves of adult wild-type mice and failure
of protein upregulation in knockout mice resulted in delayed
regrowth of regenerating axons and delayed time-course of
functional recovery. Strikingly, the functional recovery 2 months
after nerve injury was inferior in matrilin-2-deficient mice
compared with wild-type littermates, although motoneuron
survival, quality of axonal regeneration, estimated by analyses
of axonal diameters and degrees of myelination, and Schwann
cell proliferation were not influenced by the mutation. These
results show that matrilin 2 is a permissive substrate for axonal
growth and cell migration, and that it is required for successful
nerve regeneratio
Peripheral nervous system defects in erbB2 mutants following genetic rescue of heart development
The ErbB2 tyrosine kinase functions as coreceptor for the neuregulin receptors ErbB3 and ErbB4 and can
participate in signaling of EGF receptor (ErbB1), interleukin receptor gp130, and G-protein coupled receptors.
ErbB2−/− mice die at midgestation because of heart malformation. Here, we report a genetic rescue of their
heart development by myocardial expression of erbB2 cDNA that allows survival of the mutants to birth. In
rescued erbB2 mutants, Schwann cells are lacking. Motoneurons form and can project to muscle, but nerves
are poorly fasciculated and disorganized. Neuromuscular junctions form, as reflected in clustering of AChR
and postsynaptic expression of the genes encoding the a-AChR, AChE, e-AChR, and the RI subunit of the
cAMP protein kinase. However, a severe loss of motoneurons on cervical and lumbar, but not on thoracic
levels occurs. Our results define the roles of Schwann cells during motoneuron and synapse development, and
reveal different survival requirements for distinct motoneuron population
PERIOSTIN IN ALLERGY AND INFLAMMATION
Matricellular proteins are involved in the crosstalk between cells and their environment and thus play an important role in allergic and inflammatory reactions. Periostin, a matricellular protein, has several documented and multi-faceted roles in health and disease. It is differentially expressed, usually upregulated, in allergic conditions, a variety of inflammatory diseases as well as in cancer and contributes to the development and progression of these diseases. Periostin has also been shown to influence tissue remodelling, fibrosis, regeneration and repair. In allergic reactions periostin is involved in type 2 immunity and can be induced by IL-4 and IL-13 in bronchial cells. A variety of different allergic diseases, among them bronchial asthma and atopic dermatitis (AD), have been shown to be connected to periostin expression. Periostin is commonly expressed in fibroblasts and acts on epithelial cells as well as fibroblasts involving integrin and NF-κB signalling. Also direct signalling between periostin and immune cells has been reported. The deposition of periostin in inflamed, often fibrotic, tissues is further fuelling the inflammatory process. There is increasing evidence that periostin is also expressed by epithelial cells in several of the above-mentioned conditions as well as in cancer. Augmented periostin expression has also been associated with chronic inflammation such as in inflammatory bowel disease (IBD). Periostin can be expressed in a variety of different isoforms, whose functions have not been elucidated yet. This review will discuss potential functions of periostin and its different isoforms in allergy and inflammation
Role of periostin in inflammatory bowel disease development and synergistic effects mediated by the CCL5-CCR5 axis
Inflammatory bowel disease (IBD), comprising mainly Crohn's disease (CD) and ulcerative colitis (UC), is a chronic inflammatory disease of the gastrointestinal tract. In recent years, a wealth of data has been accumulated demonstrating the complex interplay of many different factors in the pathogenesis of IBD. Among these are factors impacting the epithelial barrier function, including vessel and extracellular matrix (ECM) formation, the gut microbiome (e.g., bacterial antigens), and, most importantly, the production of cytokines (pro- and anti-inflammatory) directly shaping the immune response. Patients failing to resolve the acute intestinal inflammation develop chronic inflammation. It has been shown that the expression of the matricellular protein periostin is enhanced during IBD and is one of the drivers of this disease. The C-C chemokine receptor 5 (CCR5) is engaged by the chemotactic mediators CCL3/MIP-1 alpha, CCL4/MIP-1 beta, and CCL5/RANTES. CCR5 blockade has been reported to ameliorate inflammation in a murine IBD model. Thus, both periostin and CCR5 are involved in the development of IBD. In this study, we investigated the potential crosstalk between the two signaling systems and tested a highly potent CCL5 derivative acting as a CCR5 antagonist in a murine model of IBD. We observed that the absence of periostin influences the CCR5-expressing cell population of the gut. Our data further support the notion that targeted modulation of the periostin and CCR5 signaling systems bears therapeutic potential for IBD