Pax-3 is required for the development of limb muscles: a possible role for the migration of dermomyotomal muscle progenitor cells

Development ◽  
1994 ◽  
Vol 120 (3) ◽  
pp. 603-612 ◽  
Author(s):  
E. Bober ◽  
T. Franz ◽  
H.H. Arnold ◽  
P. Gruss ◽  
P. Tremblay
Keyword(s):  
Transcription Factors ◽  
Progenitor Cells ◽  
Skeletal Muscles ◽  
Precursor Cells ◽  
Marker Genes ◽  
Specific Marker ◽  
Axial Muscles ◽  
Limb Muscles ◽  
Muscle Precursor Cells

Limb muscles in vertebrates originate from dermomyotomal cells, which during early development migrate from the ventrolateral region of somites into the limb buds. These progenitor cells do not express any muscle-specific marker genes or myogenic transcription factors until they reach their destination in the limbs. Here, we demonstrate by in situ hybridization that myogenic cells in somites and a population of presumably migratory muscle precursor cells in somatopleural tissue as well as myoblasts in the developing limbs express Pax-3. Significantly, in homozygous splotch mutant mice, which synthesize altered Pax-3 mRNA but make no normal protein, no cells positive for Pax-3 transcripts can be detected in the region of migrating limb muscle precursors or in the limb itself. In contrast, myotomal precursor cells and axial skeletal muscles contain Pax-3 transcripts also in the mutant. Interestingly, these animals fail to develop limb musculature as demonstrated by the lack of hybridization with various probes for myogenic transcription factors (Myf-5, myogenin, MyoD) but make apparently normal axial muscles. These observations suggest that Pax-3 is necessary for the formation of limb muscles, affecting either the generation of myogenic precursors in the somitic dermomyotome or the migration of these cells into the limb field.

MyoD expression marks the onset of skeletal myogenesis in Myf-5 mutant mice

Development ◽  
1994 ◽  
Vol 120 (11) ◽  
pp. 3083-3092 ◽  
Author(s):  
T. Braun ◽  
E. Bober ◽  
M.A. Rudnicki ◽  
R. Jaenisch ◽  
H.H. Arnold
Keyword(s):  
Developmental Time ◽  
Contractile Proteins ◽  
Precursor Cells ◽  
Mutant Mice ◽  
Wild Type ◽  
Myogenic Factor ◽  
Myod Gene ◽  
Muscle Precursor Cells ◽  
Myod Expression

The expression pattern of myogenic regulatory factors and myotome-specific contractile proteins was studied during embryonic development of Myf-5 mutant mice by in situ hybridization and immunohistochemistry. In contrast to somites in wild-type embryos, no expression of myogenin and Myf-6 (MRF4), or any other myotomal markers was detected in mutant animals at E9.0 and E10.0 indicating that Myf-5 plays a crucial role during this developmental period. Significantly, the onset of MyoD expression in rostral somites of E10.5 embryos was unaffected by the Myf-5 mutation suggesting that the activation of the MyoD gene occurs independently of Myf-5 at the correct developmental time. Immediately after the activation of MyoD myogenin transcripts and protein accumulated within the myotome. The first contractile proteins of the sarcomeric apparatus appeared slightly later. By E11.5 the expression of muscle markers were indistinguishable between wild-type and Myf-5 mutant mice. The migration of muscle precursor cells that leave the somites to form limb musculature was monitored in Myf-5-mutant mice by Pax-3 expression. Pax-3-positive cells were equally found in somites and limbs of E10.0 wild-type and mutant mice indicating that myogenic factor expression at the level of somites is not a prerequisite for determination and subsequent migration of limb precursor cells.

scholarly journals Evidence for a myogenic stem cell that is exhausted in dystrophic muscle

2000 ◽  
Vol 113 (12) ◽  
pp. 2299-2308 ◽  
Author(s):  
L. Heslop ◽  
J.E. Morgan ◽  
T.A. Partridge
Keyword(s):  
Skeletal Muscles ◽  
Precursor Cells ◽  
Mdx Mouse ◽  
Muscle Fibres ◽  
Significant Extent ◽  
Dystrophic Muscle ◽  
Myogenic Cells ◽  
Mouse Muscle ◽  
Muscle Precursor ◽  
Muscle Precursor Cells

Injection of the myotoxin notexin, was found to induce regeneration in muscles that had been subjected to 18 Gy of radiation. This finding was unexpected as irradiation doses of this magnitude are known to block regeneration in dystrophic (mdx) mouse muscle. To investigate this phenomenon further we subjected mdx and normal (C57Bl/10) muscle to irradiation and notexin treatment and analysed them in two ways. First by counting the number of newly regenerated myofibres expressing developmental myosin in cryosections of damaged muscles. Second, by isolating single myofibres from treated muscles and counting the number of muscle precursor cells issuing from these over 2 day and 5 day periods. After irradiation neither normal nor dystrophic muscles regenerate to any significant extent. Moreover, single myofibres cultured from such muscles produce very few muscle precursor cells and these undergo little or no proliferation. However, when irradiated normal and mdx muscles were subsequently treated with notexin, regeneration was observed. In addition, some of the single myofibres produced rapidly proliferative muscle precursor cells when cultured. This occurred more frequently, and the myogenic cells proliferated more extensively, with fibres cultured from normal compared with dystrophic muscles. Even after 25 Gy, notexin induced some regeneration but no proliferative myogenic cells remained associated with the muscle fibres. Thus, skeletal muscles contain a number of functionally distinct populations of myogenic cells. Most are radiation sensitive. However, some survive 18 Gy as proliferative myogenic cells that can be evoked by extreme conditions of muscle damage; this population is markedly diminished in muscles of the mdx mouse. A small third population survives 25 Gy and forms muscle but not proliferative myogenic cells.

scholarly journals High-Efficiency Gene Transfer Into Ex Vivo Expanded Human Hematopoietic Progenitors and Precursor Cells by Adenovirus Vectors

Blood ◽  
1998 ◽  
Vol 91 (8) ◽  
pp. 2781-2792 ◽  
Author(s):  
Beat M. Frey ◽  
Neil R. Hackett ◽  
Jeffrey M. Bergelson ◽  
Robert Finberg ◽  
Ronald G. Crystal ◽  
...  
Keyword(s):  
Progenitor Cells ◽  
High Efficiency ◽  
Ex Vivo ◽  
Hematopoietic Cells ◽  
Precursor Cells ◽  
Marker Genes ◽  
Infection Efficiency ◽  
Cd34 Cells ◽  
Hematopoietic Precursor ◽  
Low Toxicity

Replication-deficient adenoviral vectors (AdVec), which infect cycling and noncycling cells with high efficiency, low toxicity, and ease of delivery, provide ideal vehicles to study the expression of regulatory genes controlling different stages of hematopoiesis. To examine the infection efficiency of AdVec in hematopoietic precursor and progenitor cells, we used a replication-deficient adenovector expressing the humanized form of the cDNA for green fluorescent protein (AdGFP), permitting assessment of infection efficiency and kinetics of transgene expression in viable hematopoietic cells using flow cytometry and fluorescence microscopy. Flow-cytometric analysis of ex vivo expanded hematopoietic precursor cells infected with a multiplicity of infection (MOI) of 100 of AdGFP show that 78% of megakaryocytic (CD41a+ and CD42b+) cells, 82% of dendritic (CD1a+) cells, 41% of RBC precursors (glycophorin A+), and 32% of monocytic (CD14+) cells expressed GFP. Nineteen percent ± 1% of freshly isolated CD34+ cells from peripheral blood leukapheresis products infected under the same conditions expressed GFP. Morphologic evaluation of ex vivo expanded, AdGFP-infected CD34+ cells showed normal maturation. The functional capacity of AdGFP-infected CD34+ cells was analyzed by quantifying clonogeneic efficiency and proliferative capacity. Infection of CD34+ progenitor cells with MOIs of 1 to 100 did not impair clonogeneic efficiency of CD34+ cells. However, MOI greater than 100 resulted in a significant inhibition of colony-forming unit–granulocyte/granulocyte-macrophage (CFU-G/GM) formation. In sequential dilution expansion over 3 weeks (Delta assay), the cytokine-driven proliferative potential of CD34+cells was not impaired following exposure to AdGFP at MOIs of 1 to 1,000. The GFP+ population expanded 10- to 15-fold at high MOIs (500 to 1,000), indicating multiple copies of the transgene in the initially infected CD34+ cells, which were expressed in subsequent progenies. These data show that AdVec deliver transgenes with high efficiency and low toxicity to hematopoietic progenitor and precursor cells. Introduction of marker genes such as GFP into hematopoietic cells by AdVec will provide a valuable system for study of development, homing, and trafficking of hematopoietic precursor and progenitor cells in vitro and in vivo. Furthermore, these results provide insights into the design of gene therapy strategies for treatment of hematologic disorders by AdVec.

scholarly journals Heterogeneity among muscle precursor cells in adult skeletal muscles with differing regenerative capacities

1998 ◽  
Vol 212 (4) ◽  
pp. 495-508 ◽  
Author(s):  
Grace K. Pavlath ◽  
Deepa Thaloor ◽  
Thomas A. Rando ◽  
Monica Cheong ◽  
Arthur W. English ◽  
...  
Keyword(s):  
Skeletal Muscles ◽  
Precursor Cells ◽  
Muscle Precursor ◽  
Muscle Precursor Cells

scholarly journals Essential Role of p38 Mitogen-activated Protein Kinase in Cathepsin K Gene Expression during Osteoclastogenesis through Association of NFATc1 and PU.1

2004 ◽  
Vol 279 (44) ◽  
pp. 45969-45979 ◽  
Author(s):  
Masahito Matsumoto ◽  
Masakazu Kogawa ◽  
Seiki Wada ◽  
Hiroshi Takayanagi ◽  
Masafumi Tsujimoto ◽  
...  
Keyword(s):  
Gene Expression ◽  
Transcription Factors ◽  
Map Kinase ◽  
Cathepsin K ◽  
P38 Map Kinase ◽  
Nuclear Accumulation ◽  
Marker Genes ◽  
Specific Marker ◽  
Dependent Manner ◽  
Mitogen Activated Protein

The receptor activator of NF-κB ligand (RANKL) induces various osteoclast-specific marker genes during osteoclast differentiation mediated by mitogen-activated protein (MAP) kinase cascades. However, the results of transcriptional programming of an osteoclast-specific cathepsin K gene are inconclusive. Here we report the regulatory mechanisms of RANKL-induced cathepsin K gene expression during osteoclastogenesis in a p38 MAP kinase-dependent manner. The reporter gene analysis with sequential 5′-deletion constructs of the cathepsin K gene promoter indicates that limited sets of the transcription factors such as NFATc1, PU.1, and microphthalmia transcription factor indeed enhance synergistically the gene expression when overexpressed in RAW264 cells. In addition, the activation of p38 MAP kinase is required for the maximum enhancement of the gene expression. RANKL-induced NFATc1 forms a complex with PU.1 in nuclei of osteoclasts following the nuclear accumulation of NFATc1 phosphorylated by the activated p38 MAP kinase. These results suggest that the RANKL-induced cathepsin K gene expression is cooperatively regulated by the combination of the transcription factors and p38 MAP kinase in a gradual manner.

scholarly journals The Drosophila FUS ortholog cabeza promotes adult founder myoblast selection by Xrp1-dependent regulation of FGF signaling

2020 ◽  
Author(s):  
Marica Catinozzi ◽  
Moushami Mallik ◽  
Marie Frickenhaus ◽  
Marije Been ◽  
Céline Sijlmans ◽  
...  
Keyword(s):  
Dna Binding ◽  
Skeletal Muscles ◽  
Precursor Cells ◽  
Abdominal Muscles ◽  
Cell Selection ◽  
Fgf Signaling ◽  
Fgf Receptor ◽  
Muscle Precursor ◽  
Founder Cells ◽  
Muscle Precursor Cells

AbstractThe number of adult myofibers in Drosophila is determined by the number of founder myoblasts selected from a myoblast pool, a process governed by fibroblast growth factor (FGF) signaling. Here, we show that loss of cabeza (caz) function results in a reduced number of adult founder myoblasts, leading to a reduced number and misorientation of adult dorsal abdominal muscles. Genetic experiments revealed that loss of caz function in both adult myoblasts and neurons contributes to caz mutant muscle phenotypes. Selective overexpression of the FGF receptor Htl or the FGF receptor-specific signaling molecule Stumps in adult myoblasts partially rescued caz mutant muscle phenotypes, and Stumps levels were reduced in caz mutant founder myoblasts, indicating FGF pathway deregulation. In both adult myoblasts and neurons, caz mutant muscle phenotypes were mediated by increased expression levels of Xrp1, a DNA-binding protein involved in gene expression regulation. Xrp1-induced phenotypes were dependent on the DNA-binding capacity of its AT-hook motif, and increased Xrp1 levels in founder myoblasts reduced Stumps expression. Thus, control of Xrp1 expression by Caz is required for regulation of Stumps expression in founder myoblasts, resulting in correct founder myoblast selection.Author SummarySkeletal muscles mediate movement, and therefore, proper structure and function of skeletal muscles is required for respiration, locomotion, and posture. Adult muscles arise from fusion of muscle precursor cells during development. In the fruit fly Drosophila melanogaster, muscle precursor cells come in two flavors: founder cells and fusion-competent cells. The number of founder cells selected during development corresponds to the number of adult muscles formed. Here, we report that inactivation of the Drosophila caz gene results in muscle developmental defects. Loss of caz function in both muscle precursor cells and the nerve cells that innervate muscles contributes to the muscle developmental defect. At the molecular level, loss of caz function leads to increased levels of Xrp1. Xrp1 regulates the expression of many other genes, including genes that produce components of the FGF signaling pathway, which is known to be involved in founder cell selection. In all, we uncovered a novel molecular mechanism that regulates founder cell selection during muscle development.

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