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Formation, contraction, and mechanotransduction of myofribrils in cardiac development: clues from genetics.

Granados-Riveron JT, Brook JD - Biochem Res Int (2012)

Bottom Line: It is a leading infant mortality factor worldwide, caused by defective cardiac development.Mutations in transcription factors, signalling and structural molecules have been shown to contribute to the genetic component of CHD.In this paper, we summarize the genetic clues supporting this idea.

View Article: PubMed Central - PubMed

Affiliation: Institute of Genetics, Queen's Medical Centre, School of Biology, University of Nottingham, Nottingham NG7 2UH, UK.

ABSTRACT
Congenital heart disease (CHD) is the most common birth defect in humans. It is a leading infant mortality factor worldwide, caused by defective cardiac development. Mutations in transcription factors, signalling and structural molecules have been shown to contribute to the genetic component of CHD. Recently, mutations in genes encoding myofibrillar proteins expressed in the embryonic heart have also emerged as an important genetic causative factor of the disease, which implies that the contraction of the early heart primordium contributes to its morphogenesis. This notion is supported by increasing evidence suggesting that not only contraction but also formation, mechanosensing, and mechanotransduction of the cardiac myofibrillar proteins influence heart development. In this paper, we summarize the genetic clues supporting this idea.

No MeSH data available.


Related in: MedlinePlus

Schematic representation of the structures of the myofibrils responsible of contraction, sensation, and transduction of mechanical stimuli in the developing heart. Force is generated by the thick filaments formed by myosin heavy chain (amhc, MYH6, MYH7) associated with myosin regulatory (Myl7) and essential light chains and their interaction with the thin filaments, formed by actin (ACTC1, cfk) and troponin T (Tnnt2), TCAP and TMOD, amongst others. Titin spans a half of the sarcomere, from the Z-Disc (where it interacts with TCAP and MLP) to the M-band. One of its intermediate segments, the N2A-region, acts as a mechanotransducer and binds CARP, DARP, and ANKR2. The peripheral myofibrils of the cardiomyocytes are linked to integrins embedded in the cell membrane (sarcolemma) by means of the focal adhesion complexes of the costameres, formed by FAK ERK1 and ERK2, amongst others. In response to mechanical stimulation, proteins bound to titin (CARP, DARP, and ANKR2), proteins of the Z-Disc (MLP, PKCε), as well as FAK, ERK1, and ERK2, located to the focal adhesion complexes, translocate to the nucleus, where they interact with cardiac transcription factors to modify gene expression.
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fig1: Schematic representation of the structures of the myofibrils responsible of contraction, sensation, and transduction of mechanical stimuli in the developing heart. Force is generated by the thick filaments formed by myosin heavy chain (amhc, MYH6, MYH7) associated with myosin regulatory (Myl7) and essential light chains and their interaction with the thin filaments, formed by actin (ACTC1, cfk) and troponin T (Tnnt2), TCAP and TMOD, amongst others. Titin spans a half of the sarcomere, from the Z-Disc (where it interacts with TCAP and MLP) to the M-band. One of its intermediate segments, the N2A-region, acts as a mechanotransducer and binds CARP, DARP, and ANKR2. The peripheral myofibrils of the cardiomyocytes are linked to integrins embedded in the cell membrane (sarcolemma) by means of the focal adhesion complexes of the costameres, formed by FAK ERK1 and ERK2, amongst others. In response to mechanical stimulation, proteins bound to titin (CARP, DARP, and ANKR2), proteins of the Z-Disc (MLP, PKCε), as well as FAK, ERK1, and ERK2, located to the focal adhesion complexes, translocate to the nucleus, where they interact with cardiac transcription factors to modify gene expression.

Mentions: In vivo studies in chicken and mouse have shown that tropomodulin is an essential component of the myofibrils required for its proper formation [18, 19]. This protein is located in the membrane of the differentiating myocardial cell, closely associated with spectrin [18]. Once tropomyosin localizes within the thin filament, tropomodulin localizes in the pointed end of the actin filament, where it is thought to act as length stabilizer (Figure 1) [20].


Formation, contraction, and mechanotransduction of myofribrils in cardiac development: clues from genetics.

Granados-Riveron JT, Brook JD - Biochem Res Int (2012)

Schematic representation of the structures of the myofibrils responsible of contraction, sensation, and transduction of mechanical stimuli in the developing heart. Force is generated by the thick filaments formed by myosin heavy chain (amhc, MYH6, MYH7) associated with myosin regulatory (Myl7) and essential light chains and their interaction with the thin filaments, formed by actin (ACTC1, cfk) and troponin T (Tnnt2), TCAP and TMOD, amongst others. Titin spans a half of the sarcomere, from the Z-Disc (where it interacts with TCAP and MLP) to the M-band. One of its intermediate segments, the N2A-region, acts as a mechanotransducer and binds CARP, DARP, and ANKR2. The peripheral myofibrils of the cardiomyocytes are linked to integrins embedded in the cell membrane (sarcolemma) by means of the focal adhesion complexes of the costameres, formed by FAK ERK1 and ERK2, amongst others. In response to mechanical stimulation, proteins bound to titin (CARP, DARP, and ANKR2), proteins of the Z-Disc (MLP, PKCε), as well as FAK, ERK1, and ERK2, located to the focal adhesion complexes, translocate to the nucleus, where they interact with cardiac transcription factors to modify gene expression.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3376475&req=5

fig1: Schematic representation of the structures of the myofibrils responsible of contraction, sensation, and transduction of mechanical stimuli in the developing heart. Force is generated by the thick filaments formed by myosin heavy chain (amhc, MYH6, MYH7) associated with myosin regulatory (Myl7) and essential light chains and their interaction with the thin filaments, formed by actin (ACTC1, cfk) and troponin T (Tnnt2), TCAP and TMOD, amongst others. Titin spans a half of the sarcomere, from the Z-Disc (where it interacts with TCAP and MLP) to the M-band. One of its intermediate segments, the N2A-region, acts as a mechanotransducer and binds CARP, DARP, and ANKR2. The peripheral myofibrils of the cardiomyocytes are linked to integrins embedded in the cell membrane (sarcolemma) by means of the focal adhesion complexes of the costameres, formed by FAK ERK1 and ERK2, amongst others. In response to mechanical stimulation, proteins bound to titin (CARP, DARP, and ANKR2), proteins of the Z-Disc (MLP, PKCε), as well as FAK, ERK1, and ERK2, located to the focal adhesion complexes, translocate to the nucleus, where they interact with cardiac transcription factors to modify gene expression.
Mentions: In vivo studies in chicken and mouse have shown that tropomodulin is an essential component of the myofibrils required for its proper formation [18, 19]. This protein is located in the membrane of the differentiating myocardial cell, closely associated with spectrin [18]. Once tropomyosin localizes within the thin filament, tropomodulin localizes in the pointed end of the actin filament, where it is thought to act as length stabilizer (Figure 1) [20].

Bottom Line: It is a leading infant mortality factor worldwide, caused by defective cardiac development.Mutations in transcription factors, signalling and structural molecules have been shown to contribute to the genetic component of CHD.In this paper, we summarize the genetic clues supporting this idea.

View Article: PubMed Central - PubMed

Affiliation: Institute of Genetics, Queen's Medical Centre, School of Biology, University of Nottingham, Nottingham NG7 2UH, UK.

ABSTRACT
Congenital heart disease (CHD) is the most common birth defect in humans. It is a leading infant mortality factor worldwide, caused by defective cardiac development. Mutations in transcription factors, signalling and structural molecules have been shown to contribute to the genetic component of CHD. Recently, mutations in genes encoding myofibrillar proteins expressed in the embryonic heart have also emerged as an important genetic causative factor of the disease, which implies that the contraction of the early heart primordium contributes to its morphogenesis. This notion is supported by increasing evidence suggesting that not only contraction but also formation, mechanosensing, and mechanotransduction of the cardiac myofibrillar proteins influence heart development. In this paper, we summarize the genetic clues supporting this idea.

No MeSH data available.


Related in: MedlinePlus