135 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
Transcription factor Sox10 orchestrates activity of a neural crest-specific enhancer in the vicinity of its gene
The Sox10 transcription factor is a central regulator of vertebrate neural crest and nervous system development. Its expression is likely controlled by multiple enhancer elements, among them U3 (alternatively known as MCS4). Here we analyze U3 activity to obtain deeper insights into Sox10 function and expression in the neural crest and its derivatives. U3 activity strongly depends on the presence of Sox10 that regulates its own expression as commonly observed for important developmental regulators. Sox10 bound directly as monomer to at least three sites in U3, whereas a fourth site preferred dimers. Deletion of these sites efficiently reduced U3 activity in transfected cells and transgenic mice. In stimulating the U3 enhancer, Sox10 synergized with many other transcription factors present in neural crest and developing peripheral nervous system including Pax3, FoxD3, AP2α, Krox20 and Sox2. In case of FoxD3, synergism involved Sox10-dependent recruitment to the U3 enhancer, while Sox10 and AP2α each had to bind to the regulatory region. Our study points to the importance of autoregulatory activity and synergistic interactions for maintenance of Sox10 expression and functional activity of Sox10 in the neural crest regulatory network
Essential Role of Gab1 for Signaling by the C-Met Receptor in Vivo
The docking protein Gab1 binds phosphorylated c-Met receptor tyrosine kinase directly and mediates signals of c-Met in cell culture. Gab1 is phosphorylated by c-Met and by other receptor and nonreceptor tyrosine kinases. Here, we report the functional analysis of Gab1 by targeted mutagenesis in the mouse, and compare the phenotypes of the Gab1 and c-Met mutations. Gab1 is essential for several steps in development: migration of myogenic precursor cells into the limb anlage is impaired in Gab1−/− embryos. As a consequence, extensor muscle groups of the forelimbs are virtually absent, and the flexor muscles reach less far. Fewer hindlimb muscles exist, which are smaller and disorganized. Muscles in the diaphragm, which also originate from migratory precursors, are missing. Moreover, Gab1−/− embryos die in a broad time window between E13.5 and E18.5, and display reduced liver size and placental defects. The labyrinth layer, but not the spongiotrophoblast layer, of the placenta is severely reduced, resulting in impaired communication between maternal and fetal circulation. Thus, extensive similarities between the phenotypes of c-Met and HGF/SF mutant mice exist, and the muscle migration phenotype is even more pronounced in Gab1−/−:c-Met+/− embryos. This is genetic evidence that Gab1 is essential for c-Met signaling in vivo. Analogy exists to signal transmission by insulin receptors, which require IRS1 and IRS2 as specific docking proteins
Phox2b function in the enteric nervous system is conserved in zebrafish and is sox10-dependent
Zebrafish lacking functional sox10 have defects in non-ectomesenchymal neural crest derivatives including the enteric nervous system (ENS) and as such provide an animal model for human Waardenburg Syndrome IV. Here, we characterize zebrafish phox2b as a functionally conserved marker of the developing ENS. We show that morpholino-mediated knockdown of Phox2b generates fish modeling Hirschsprung disease. Using markers, including phox2b, we investigate the ontogeny of the sox10 ENS phenotype. As previously shown for melanophore development, ENS progenitor fate specification fails in these mutant fish. However, in addition, we trace back the sox10 mutant ENS defect to an even earlier time point, finding that most neural crest cells fail to migrate ventrally to the gut primordium. (c) 2005 Elsevier Ireland Ltd. All rights reserved.Medical Research Council [G0300415
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