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Myogenesis is the formation of skeletal muscular tissue, particularly during embryonic development. Muscle fibers generally form through the fusion of
precursor Precursor or Precursors may refer to: * Precursor (religion), a forerunner, predecessor ** The Precursor, John the Baptist Science and technology * Precursor (bird), a hypothesized genus of fossil birds that was composed of fossilized parts of u ...
myoblasts into
multinucleated Multinucleate cells (also known as multinucleated or polynuclear cells) are eukaryotic cells that have more than one nucleus per cell, i.e., multiple nuclei share one common cytoplasm. Mitosis in multinucleate cells can occur either in a coordinat ...
fibers called ''myotubes''. In the early development of an embryo, myoblasts can either proliferate, or differentiate into a myotube. What controls this choice in vivo is generally unclear. If placed in cell culture, most myoblasts will proliferate if enough
fibroblast growth factor Fibroblast growth factors (FGF) are a family of cell signalling proteins produced by macrophages; they are involved in a wide variety of processes, most notably as crucial elements for normal development in animal cells. Any irregularities in their ...
(FGF) or another growth factor is present in the medium surrounding the cells. When the growth factor runs out, the myoblasts cease division and undergo terminal differentiation into myotubes. Myoblast differentiation proceeds in stages. The first stage, involves cell cycle exit and the commencement of expression of certain genes. The second stage of differentiation involves the alignment of the myoblasts with one another. Studies have shown that even rat and chick myoblasts can recognise and align with one another, suggesting evolutionary conservation of the mechanisms involved. The third stage is the actual cell fusion itself. In this stage, the presence of
calcium Calcium is a chemical element with the symbol Ca and atomic number 20. As an alkaline earth metal, calcium is a reactive metal that forms a dark oxide-nitride layer when exposed to air. Its physical and chemical properties are most similar t ...
ions is critical. Fusion in humans is aided by a set of
metalloproteinase A metalloproteinase, or metalloprotease, is any protease enzyme whose catalytic mechanism involves a metal. An example is ADAM12 which plays a significant role in the fusion of muscle cells during embryo development, in a process known as myo ...
s coded for by the ''
ADAM12 Disintegrin and metalloproteinase domain-containing protein 12 (previously Meltrin) is an enzyme that in humans is encoded by the ''ADAM12'' gene. ADAM12 has two splice variants: ADAM12-L, the long form, has a transmembrane region and ADAM12-S, a ...
''
gene In biology, the word gene (from , ; "... Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a b ...
, and a variety of other proteins. Fusion involves recruitment of
actin Actin is a family of globular multi-functional proteins that form microfilaments in the cytoskeleton, and the thin filaments in muscle fibrils. It is found in essentially all eukaryotic cells, where it may be present at a concentration of ov ...
to the plasma membrane, followed by close apposition and creation of a pore that subsequently rapidly widens. Novel genes and their protein products that are expressed during the process are under active investigation in many laboratories. They include: # Myocyte enhancer factors (MEFs), which promote myogenesis. #
Serum response factor Serum response factor, also known as SRF, is a transcription factor protein. Function Serum response factor is a member of the MADS (MCM1, Agamous, Deficiens, and SRF) box superfamily of transcription factors. This protein binds to the serum ...
(SRF) plays a central role during myogenesis, being required for the expression of striated alpha-actin genes. Expression of skeletal
alpha-actin Actin is a family of globular multi-functional proteins that form microfilaments in the cytoskeleton, and the thin filaments in muscle fibrils. It is found in essentially all eukaryotic cells, where it may be present at a concentration of over ...
is also regulated by the androgen receptor; steroids can thereby regulate myogenesis. #
Myogenic regulatory factors Myogenic regulatory factors (MRF) are basic helix-loop-helix (bHLH) transcription factors that regulate myogenesis: MyoD, Myf5, myogenin, and MRF4. These proteins contain a conserved basic DNA binding domain that binds the E box DNA motif. They ...
(MRFs): MyoD, Myf5, Myf6 and Myogenin.


Overview

There are a number of stages (listed below) of muscle development, or myogenesis. Each stage has various associated genetic factors lack of which will result in muscular defects.


Stages


Delamination

Associated Genetic Factors:
PAX3 The PAX3 (paired box gene 3) gene encodes a member of the paired box or PAX family of transcription factors. The PAX family consists of nine human (PAX1-PAX9) and nine mouse (Pax1-Pax9) members arranged into four subfamilies. Human PAX3 and mouse ...
and
c-Met c-Met, also called tyrosine-protein kinase Met or hepatocyte growth factor receptor (HGFR), is a protein that in humans is encoded by the ''MET'' gene. The protein possesses tyrosine kinase activity. The primary single chain precursor protein i ...

Mutations in PAX3 can cause a failure in c-Met expression. Such a mutation would result in a lack of lateral migration. PAX3 mediates the transcription of c-Met and is responsible for the activation of MyoD expression—one of the functions of MyoD is to promote the regenerative ability of
satellite cells Myosatellite cells, also known as satellite cells, muscle stem cells or MuSCs, are small multipotent cells with very little cytoplasm found in mature muscle. Satellite cells are precursors to skeletal muscle cells, able to give rise to satellite ...
(described below). PAX3 is generally expressed at its highest levels during embryonic development and is expressed at a lesser degree during the fetal stages; it is expressed in migrating hypaxial cells and dermomyotome cells, but is not expressed at all during the development of
facial muscle The facial muscles are a group of striated skeletal muscles supplied by the facial nerve (cranial nerve VII) that, among other things, control facial expression. These muscles are also called mimetic muscles. They are only found in mammals, alth ...
. Mutations in Pax3 can cause a variety of complications including
Waardenburg syndrome Waardenburg syndrome is a group of rare genetic conditions characterised by at least some degree of congenital hearing loss and pigmentation deficiencies, which can include bright blue eyes (or one blue eye and one brown eye), a white foreloc ...
I and III as well as craniofacial-deafness-hand syndrome. Waardenburg syndrome is most often associated with congenital disorders involving the intestinal tract and spine, an elevation of the scapula, among other symptoms. Each stage has various associated genetic factors without which will result in muscular defects.


Migration

Associated Genetic Factors:
c-Met c-Met, also called tyrosine-protein kinase Met or hepatocyte growth factor receptor (HGFR), is a protein that in humans is encoded by the ''MET'' gene. The protein possesses tyrosine kinase activity. The primary single chain precursor protein i ...
/ HGF and LBX1
Mutations in these genetic factors causes a lack of migration. LBX1 is responsible for the development and organization of muscles in the dorsal forelimb as well as the movement of dorsal muscles into the limb following
delamination Delamination is a mode of failure where a material fractures into layers. A variety of materials including laminate composites and concrete can fail by delamination. Processing can create layers in materials such as steel formed by rolling a ...
. Without LBX1, limb muscles will fail to form properly; studies have shown that hindlimb muscles are severely affected by this deletion while only flexor muscles form in the forelimb muscles as a result of ventral muscle migration. c-Met is a
tyrosine kinase receptor Receptor tyrosine kinases (RTKs) are the high-affinity cell surface receptors for many polypeptide growth factors, cytokines, and hormones. Of the 90 unique tyrosine kinase genes identified in the human genome, 58 encode receptor tyrosine kinase ...
that is required for the survival and proliferation of migrating myoblasts. A lack of c-Met disrupts secondary myogenesis and—as in LBX1—prevents the formation of limb musculature. It is clear that c-Met plays an important role in delamination and proliferation in addition to migration. PAX3 is needed for the transcription of c-Met.


Proliferation

Associated Genetic Factors:
PAX3 The PAX3 (paired box gene 3) gene encodes a member of the paired box or PAX family of transcription factors. The PAX family consists of nine human (PAX1-PAX9) and nine mouse (Pax1-Pax9) members arranged into four subfamilies. Human PAX3 and mouse ...
,
c-Met c-Met, also called tyrosine-protein kinase Met or hepatocyte growth factor receptor (HGFR), is a protein that in humans is encoded by the ''MET'' gene. The protein possesses tyrosine kinase activity. The primary single chain precursor protein i ...
,
Mox2 Mixed oxide fuel, commonly referred to as MOX fuel, is nuclear fuel that contains more than one oxide of fissile material, usually consisting of plutonium blended with natural uranium, reprocessed uranium, or depleted uranium. MOX fuel is an alt ...
,
MSX1 Homeobox protein MSX-1, is a protein that in humans is encoded by the ''MSX1'' gene. MSX1 transcripts are not only found in thyrotrope-derived TSH cells, but also in the TtT97 thyrotropic tumor, which is a well differentiated hyperplastic tissue ...
, Six, Myf5, and
MyoD MyoD, also known as myoblast determination protein 1, is a protein in animals that plays a major role in regulating muscle differentiation. MyoD, which was discovered in the laboratory of Harold M. Weintraub, belongs to a family of proteins kno ...
Mox2 (also referred to as MEOX-2) plays an important role in the induction of mesoderm and
regional specification In the field of developmental biology, regional differentiation is the process by which different areas are identified in the development of the early embryo. The process by which the cells become specified differs between organisms. Cell fate det ...
. Impairing the function of Mox2 will prevent the proliferation of myogenic precursors and will cause abnormal patterning of limb muscles. Specifically, studies have shown that hindlimbs are severely reduced in size while specific forelimb muscles will fail to form. Myf5 is required for proper myoblast proliferation. Studies have shown that mice muscle development in the intercostal and paraspinal regions can be delayed by inactivating Myf-5. Myf5 is considered to be the earliest expressed regulatory factor gene in myogenesis. If Myf-5 and MyoD are both inactivated, there will be a complete absence of skeletal muscle. These consequences further reveal the complexity of myogenesis and the importance of each genetic factor in proper muscle development.


Determination

Associated Genetic Factors: Myf5 and
MyoD MyoD, also known as myoblast determination protein 1, is a protein in animals that plays a major role in regulating muscle differentiation. MyoD, which was discovered in the laboratory of Harold M. Weintraub, belongs to a family of proteins kno ...

One of the most important stages in myogenesis determination requires both Myf5 and MyoD to function properly in order for myogenic cells to progress normally. Mutations in either associated genetic factor will cause the cells to adopt non-muscular phenotypes. As stated earlier, the combination of Myf5 and MyoD is crucial to the success of myogenesis. Both MyoD and Myf5 are members of the myogenic bHLH (basic helix-loop-helix) proteins transcription factor family. Cells that make myogenic bHLH transcription factors (including MyoD or Myf5) are committed to development as a muscle cell. Consequently, the simultaneous deletion of Myf5 and MyoD also results in a complete lack of skeletal muscle formation. Research has shown that MyoD directly activates its own gene; this means that the protein made binds the ''myoD'' gene and continues a cycle of MyoD protein production. Meanwhile, Myf5 expression is regulated by Sonic hedgehog,
Wnt1 Proto-oncogene Wnt-1, or Proto-oncogene Int-1 homolog is a protein that in humans is encoded by the () gene. The WNT gene family consists of structurally related genes that encode secreted signaling proteins. These proteins have been implicated ...
, and MyoD itself. By noting the role of MyoD in regulating Myf5, the crucial interconnectedness of the two genetic factors becomes clear.


Differentiation

Associated genetic factors:
Myogenin Myogenin, is a transcriptional activator encoded by the MYOG gene. Myogenin is a muscle-specific basic-helix-loop-helix (bHLH) transcription factor involved in the coordination of skeletal muscle development or myogenesis and repair. Myogenin is ...
,
Mcf2 The DBL proto-oncogene is a protein that in humans is encoded by the ''MCF2'' gene. The commonly-used name DBL is derived from “diffuse B-cell lymphoma”, the cancer type where this gene was first identified as an oncogene An oncogene is a ...
, Six,
MyoD MyoD, also known as myoblast determination protein 1, is a protein in animals that plays a major role in regulating muscle differentiation. MyoD, which was discovered in the laboratory of Harold M. Weintraub, belongs to a family of proteins kno ...
, and Myf6
Mutations in these associated genetic factors will prevent myocytes from advancing and maturing.
Myogenin Myogenin, is a transcriptional activator encoded by the MYOG gene. Myogenin is a muscle-specific basic-helix-loop-helix (bHLH) transcription factor involved in the coordination of skeletal muscle development or myogenesis and repair. Myogenin is ...
(also known as Myf4) is required for the fusion of myogenic precursor cells to either new or previously existing fibers. In general, myogenin is associated with amplifying expression of genes that are already being expressed in the organism. Deleting myogenin results in nearly complete loss of differentiated muscle fibers and severe loss of skeletal muscle mass in the lateral/ventral body wall. Myf-6 (also known as MRF4 or Herculin) is important to myotube differentiation and is specific to skeletal muscle. Mutations in Myf-6 can provoke disorders including
centronuclear myopathy Centronuclear myopathies (CNM) are a group of congenital myopathies where cell nuclei are abnormally located in the center of muscle cells instead of their normal location at the periphery. Symptoms of CNM include severe hypotonia, hypoxia-requi ...
and Becker muscular dystrophy.


Specific muscle formation

Associated genetic factors: LBX1 and
Mox2 Mixed oxide fuel, commonly referred to as MOX fuel, is nuclear fuel that contains more than one oxide of fissile material, usually consisting of plutonium blended with natural uranium, reprocessed uranium, or depleted uranium. MOX fuel is an alt ...

In specific muscle formation, mutations in associated genetic factors begin to affect specific muscular regions. Because of its large responsibility in the movement of dorsal muscles into the limb following delamination, mutation or deletion of Lbx1 results in defects in extensor and hindlimb muscles. As stated in the Proliferation section, Mox2 deletion or mutation causes abnormal patterning of limb muscles. The consequences of this abnormal patterning include severe reduction in size of hindlimbs and complete absence of forelimb muscles.


Satellite cells

Associated genetic factors:
PAX7 Paired box protein Pax-7 is a protein that in humans is encoded by the ''PAX7'' gene. Function Pax-7 plays a role in neural crest development and gastrulation, and it is an important factor in the expression of neural crest markers such as Slug ...

Mutations in Pax7 will prevent the formation of satellite cells and, in turn, prevent postnatal muscle growth.
Satellite cells Myosatellite cells, also known as satellite cells, muscle stem cells or MuSCs, are small multipotent cells with very little cytoplasm found in mature muscle. Satellite cells are precursors to skeletal muscle cells, able to give rise to satellite ...
are described as quiescent myoblasts and neighbor muscle fiber
sarcolemma The sarcolemma (''sarco'' (from ''sarx'') from Greek; flesh, and ''lemma'' from Greek; sheath) also called the myolemma, is the cell membrane surrounding a skeletal muscle fiber or a cardiomyocyte. It consists of a lipid bilayer and a thin oute ...
. They are crucial for the repair of muscle, but have a very limited ability to replicate. Activated by stimuli such as injury or high mechanical load, satellite cells are required for
muscle regeneration Skeletal muscles (commonly referred to as muscles) are organs of the vertebrate muscular system and typically are attached by tendons to bones of a skeleton. The muscle cells of skeletal muscles are much longer than in the other types of muscl ...
in adult organisms. In addition, satellite cells have the capability to also differentiate into bone or fat. In this way, satellite cells have an important role in not only muscle development, but in the maintenance of muscle through adulthood.


Skeletal muscle

During embryogenesis, the
dermomyotome The somites (outdated term: primitive segments) are a set of bilaterally paired blocks of paraxial mesoderm that form in the embryogenesis, embryonic stage of somitogenesis, along the head-to-tail axis in segmentation (biology), segmented animals. ...
and/or
myotome A myotome is the group of muscles that a single spinal nerve innervates. Similarly a dermatome is an area of skin that a single nerve innervates with sensory fibers. Myotomes are separated by myosepta (singular: myoseptum). In vertebrate embryon ...
in the
somites The somites (outdated term: primitive segments) are a set of bilaterally paired blocks of paraxial mesoderm that form in the embryonic stage of somitogenesis, along the head-to-tail axis in segmented animals. In vertebrates, somites subdivide i ...
contain the myogenic progenitor cells that will evolve into the prospective skeletal muscle. The determination of dermomyotome and myotome is regulated by a gene regulatory network that includes a member of the
T-box T-box refers to a group of transcription factors involved in embryonic limb and heart development. Every T-box protein has a relatively large DNA-binding domain, generally comprising about a third of the entire protein that is both necessary a ...
family, tbx6, ripply1, and mesp-ba. Skeletal myogenesis depends on the strict regulation of various gene subsets in order to differentiate the myogenic progenitors into myofibers. Basic helix-loop-helix (bHLH) transcription factors, MyoD, Myf5, myogenin, and MRF4 are critical to its formation. MyoD and Myf5 enable the differentiation of myogenic progenitors into myoblasts, followed by myogenin, which differentiates the myoblast into myotubes. MRF4 is important for blocking the transcription of muscle-specific promoters, enabling skeletal muscle progenitors to grow and proliferate before differentiating. There are a number of events that occur in order to propel the specification of muscle cells in the somite. For both the lateral and medial regions of the somite,
paracrine Paracrine signaling is a form of cell signaling, a type of cellular communication in which a cell produces a signal to induce changes in nearby cells, altering the behaviour of those cells. Signaling molecules known as paracrine factors diffuse over ...
factors induce myotome cells to produce MyoD protein—thereby causing them to develop as muscle cells. A transcription factor (
TCF4 Transcription factor 4 (TCF-4) also known as immunoglobulin transcription factor 2 (ITF-2) is a protein that in humans is encoded by the TCF4 gene located on chromosome 18q21.2. Function TCF4 proteins act as transcription factors which will ...
) of connective tissue fibroblasts is involved in the regulation of myogenesis. Specifically, it regulates the type of muscle fiber developed and its maturations. Low levels of TCF4 promote both slow and fast myogenesis, overall promoting the maturation of muscle fiber type. Thereby this shows the close relationship of muscle with connective tissue during the embryonic development. Regulation of myogenic differentiation is controlled by two pathways: the
phosphatidylinositol 3-kinase Phosphoinositide 3-kinases (PI3Ks), also called phosphatidylinositol 3-kinases, are a family of enzymes involved in cellular functions such as cell growth, proliferation, differentiation, motility, survival and intracellular trafficking, which i ...
/Akt pathway and the Notch/Hes pathway, which work in a collaborative manner to suppress MyoD transcription. The O subfamily of the forkhead proteins (
FOXO FOX (forkhead box) proteins are a family of transcription factors that play important roles in regulating the expression of genes involved in cell growth, proliferation, differentiation, and longevity. Many FOX proteins are important to embryonic ...
) play a critical role in regulation of myogenic differentiation as they stabilize Notch/Hes binding. Research has shown that knockout of FOXO1 in mice increases MyoD expression, altering the distribution of fast-twitch and slow-twitch fibers.


Muscle fusion

Primary muscle fibers originate from primary myoblasts and tend to develop into slow muscle fibers. Secondary muscle fibers then form around the primary fibers near the time of innervation. These muscle fibers form from secondary myoblasts and usually develop as fast muscle fibers. Finally, the muscle fibers that form later arise from satellite cells. Two genes significant in muscle fusion are
Mef2 In the field of molecular biology, myocyte enhancer factor-2 (Mef2) proteins are a family of transcription factors which through control of gene expression are important regulators of cellular differentiation and consequently play a critical r ...
and the
twist transcription factor Twist-related protein 1 (TWIST1) also known as class A basic helix–loop–helix protein 38 (bHLHa38) is a basic helix-loop-helix transcription factor that in humans is encoded by the ''TWIST1'' gene. Function Basic helix-loop-helix (bHLH) tr ...
. Studies have shown knockouts for Mef2C in mice lead to muscle defects in cardiac and smooth muscle development, particularly in fusion. The twist gene plays a role in muscle differentiation. The
SIX1 Homeobox protein SIX1 (Sine oculis homeobox homolog 1) is a protein that in humans is encoded by the ''SIX1'' gene. Function The vertebrate SIX genes are homologs of the Drosophila 'sine oculis' (so) gene, which is expressed primarily in the ...
gene plays a critical role in hypaxial muscle differentiation in myogenesis. In mice lacking this gene, severe muscle hypoplasia affected most of the body muscles, specifically hypaxial muscles.


Protein synthesis and actin heterogeneity

There are 3 types of proteins produced during myogenesis. Class A proteins are the most abundant and are synthesized continuously throughout myogenesis. Class B proteins are proteins that are initiated during myogenesis and continued throughout development. Class C proteins are those synthesized at specific times during development. Also 3 different forms of
actin Actin is a family of globular multi-functional proteins that form microfilaments in the cytoskeleton, and the thin filaments in muscle fibrils. It is found in essentially all eukaryotic cells, where it may be present at a concentration of ov ...
were identified during myogenesis.
Sim2 Single-minded homolog 2 is a protein that in humans is encoded by the ''SIM2'' gene. It plays a major role in the development of the central nervous system midline as well as the construction of the face and head. Function SIM1 and SIM2 genes ...
, a BHLH-Pas transcription factor, inhibits transcription by active repression and displays enhanced expression in ventral limb muscle masses during chick and mouse embryonic development. It accomplishes this by repressing MyoD transcription by binding to the enhancer region, and prevents premature myogenesis.
Delta1 Delta-like protein 1 is a protein that in humans is encoded by the ''DLL1'' gene. Function DLL1 is a human homolog of the Notch Delta ligand and is a member of the delta/serrate/jagged family. It plays a role in mediating cell fate decisions d ...
expression in
neural crest cells Neural crest cells are a temporary group of cells unique to vertebrates that arise from the embryonic ectoderm germ layer, and in turn give rise to a diverse cell lineage—including melanocytes, craniofacial cartilage and bone, smooth muscle, ...
is necessary for muscle differentiation of the
somites The somites (outdated term: primitive segments) are a set of bilaterally paired blocks of paraxial mesoderm that form in the embryonic stage of somitogenesis, along the head-to-tail axis in segmented animals. In vertebrates, somites subdivide i ...
, through the Notch signaling pathway. Gain and loss of this ligand in
neural crest cells Neural crest cells are a temporary group of cells unique to vertebrates that arise from the embryonic ectoderm germ layer, and in turn give rise to a diverse cell lineage—including melanocytes, craniofacial cartilage and bone, smooth muscle, ...
results in delayed or premature myogenesis.


Techniques

The significance of alternative splicing was elucidated using microarrary analysis of differentiating
C2C12 C2C12 is an immortalized mouse myoblast cell line. The C2C12 cell line is a subclone of myoblasts that were originally obtained by Yaffe and Saxel at the Weizmann Institute of Science in Israel in 1977. Developed for ''in vitro'' studies of myo ...
myoblasts. 95 alternative splicing events occur during
C2C12 C2C12 is an immortalized mouse myoblast cell line. The C2C12 cell line is a subclone of myoblasts that were originally obtained by Yaffe and Saxel at the Weizmann Institute of Science in Israel in 1977. Developed for ''in vitro'' studies of myo ...
differentiation in myogenesis. Therefore, alternative splicing is necessary in myogenesis.


Systems approach

Systems approach is a method used to study myogenesis, which manipulates a number of different techniques like
high-throughput screening High-throughput screening (HTS) is a method for scientific experimentation especially used in drug discovery and relevant to the fields of biology, materials science and chemistry. Using robotics, data processing/control software, liquid handling ...
technologies, genome wide cell-based
assays An assay is an investigative (analytic) procedure in laboratory medicine, mining, pharmacology, environmental biology and molecular biology for qualitatively assessing or quantitatively measuring the presence, amount, or functional activity of a ...
, and bioinformatics, to identify different factors of a system. This has been specifically used in the investigation of skeletal muscle development and the identification of its regulatory network. Systems approach using
high-throughput sequencing DNA sequencing is the process of determining the nucleic acid sequence – the order of nucleotides in DNA. It includes any method or technology that is used to determine the order of the four bases: adenine, guanine, cytosine, and thymine. Th ...
and
ChIP-chip ChIP-on-chip (also known as ChIP-chip) is a technology that combines chromatin immunoprecipitation ('ChIP') with DNA microarray (''"chip"''). Like regular ChIP, ChIP-on-chip is used to investigate interactions between proteins and DNA '' in viv ...
analysis has been essential in elucidating the targets of myogenic regulatory factors like MyoD and myogenin, their inter-related targets, and how MyoD acts to alter the epigenome in myoblasts and myotubes. This has also revealed the significance of PAX3 in myogenesis, and that it ensures the survival of myogenic progenitors. This approach, using cell based high-throughput transfection assay and whole-mount
in situ hybridization ''In situ'' hybridization (ISH) is a type of hybridization that uses a labeled complementary DNA, RNA or modified nucleic acids strand (i.e., probe) to localize a specific DNA or RNA sequence in a portion or section of tissue (''in situ'') o ...
, was used in identifying the myogenetic regulator RP58, and the tendon differentiation gene, Mohawk homeobox.


References


External links


Gilbert, Scott F. ''Developmental Biology'', Sixth Edition - Myogenesis - The Development of Muscle
{{Muscular physiology Animal developmental biology Muscular system