Where Notch and Wnt signaling meet. The presenilin hub.
Newest Articles · Current Issue · Archive · Subject Collections · Meeting Collections · Reviews & Opinions · Editorials · In Focus · People & Ideas · Spotlights. The presenilins (PSs) are part of the molecular machinery responsible for cleaving proteins like the β-amyloid precursor protein (APP) and Notch in the plane of. Different authors provided scientific evidences regarding a sequential and direct link between Notch and Wnt signaling pathways in tuning.
Several studies have recognized the central role of Notch-mediated signaling also in cardiac development [ 37 ]. In cardiomyocytes, the expression of Notch is not constant over time; it is high in embryonic and proliferating immature cells but disappears when the cells lose the ability to proliferate [ 38 ]. The prolonged activation of Notch in adult cardiomyocytes may have different consequences. Crosstalk between Notch and Wnt has also been described [ 4145 — 47 ].
Mice deficient for Wnt2 displayed vascular abnormalities including defective placental vasculature [ 49 ]. Knock-out mice for the Wnt receptor gene, Frizzled5, died in utero due to defects in yolk sac angiogenesis [ 50 ].
Dvl has a dual role: Thus Dv1 is a key regulator of cell-fate decisions in which Wnt and Notch have opposing effects [ 54 ]. PKC is a family of -dependent and -independent isoforms that have different distributions in various blood vessels, and individual members can have different roles in a plethora of biological and pathological events [ 54 — 56 ].
For example, in both the skin and mammary gland, Wnt signaling promotes the maintenance of the stem cell fate whereas Notch signaling promotes lineage commitment and differentiation [ 5458 — 60 ].
In this case, the inhibition of Notch signaling would help to maintain the stem cell population. The Notch and Wnt pathways also have opposing effects at later steps within a cell lineage. For example, Notch and Wnt signaling influence terminal differentiation within the intestinal epithelium, with Notch activity biasing cells towards the absorptive fate and Wnt signaling favouring secretory cell differentiation [ 61 — 64 ].
Wnt pathway activation promotes neuronal differentiation and inhibits Notch signaling of primary human glioblastoma multiforme- GBM- derived cells [ 65 ].
Disregulation of Wnt-Notch signaling crosstalk alters early vascular development. This, in turn, prevents a correct endothelial cell differentiation, altering vascular remodeling and arteriovenous specification. Wnt signaling has been identified as a downstream target of Notch1 that regulates expression of cardiac transcription factors during mouse cardiogenesis and is essential for cardiac development facilitating transcription of target genes involved in cell fate regulation [ 7576 ].
Integrin signaling is linked to Wnt signaling. ILK can also activate Notch signaling. Stretch-induced mechanotransduction in VSMCs is known to be regulated by redox signaling initiated by stretch-induced activation of Nox and consequently increased ROS level [ 8889 ]. Catalase, an antioxidant enzyme that degrades H2O2, prevented the stretch-induced translocation of Notch3 to the nucleus, increased Hes1 expression, and decreased Notch3 extracellular domain.
In bone marrow-derived mesenchymal stem cells Boopathy et al. These results are in line with other authors: A recent study by Funato et al. Furthermore Kajla et al. Msx2, a profibrotic, proosteogenic transcription factor upregulates the expression of multiple Wnt ligands during angiogenesis [ 99 ] and enhances aortic canonical Wnt signaling [ ]. APC mutation causes Wnt signaling activation and is commonly found in colorectal cancer [ ].
Accordingly, increased ROS might contribute to tumorigenesis by activating specific signaling pathways in different cell types [ ], one of which is Wnt signaling. Conclusion and Future Perspectives ROS have long been deemed as noxious molecules in cardiovascular diseases, including systemic and pulmonary hypertension, atherosclerosis, cardiac hypertrophy, and heart failure. With years of efforts, ROS are becoming increasingly recognized as important modulator for a variety of biological functions and pathophysiological states.
Recent evidences suggest an even more significant role of ROS: A clear distinction between Notch and Wnt responses is vital for appropriate and robust cell-fate decisions, and ROS modulation of these signaling pathways would provide clues for clinical strategies and drug discovery targeting cardiovascular diseases and cancer. Above we have discussed how ROS modulation of Notch and Wnt signaling regulates vascular development in different aspects, including stem cells differentiation, angiogenesis, VEGF signaling, endothelial as well as cardiac progenitor cells recruitment, and vascular cell migration.
Nonetheless, more details regarding the ROS signaling and pathophysiological functions remain to be elucidated. While Wnt is critical for muscle development as evident in no dermomyotome formation or Myf5 expression in embryonic Wnt1 and Wnt3a knockout mice, Wnt also contributes postnatal muscle regeneration 9093 Wnt's main role during muscle regeneration is myoblast differentiation and myotube fusion 99 - Premature myogenic differentiation occurs in freeze-injured muscle injected with Wnt3a Myogenesis consists of a series of orchestrated events that require communication of a variety of signaling pathways when transitioning from the phases of satellite cell activation to myoblast proliferation and differentiation and finally, myotube formation.
Notch and Wnt interact during muscle development as well as during postnatal myogenesis and it is plausible that this crosstalk contributes to the stage transitions during adult muscle repair 93 It is suggested that Notch activity presides during myoblast proliferation after which there is a temporal switch to Wnt signaling and subsequent myoblast differentiation and fusion into myotubes When Notch inhibitors are administered during the differentiation phase there is no acceleration of muscle regeneration, further supporting the notion that Notch signaling does not participate in the later stages of muscle repair In addition, during the early stages of muscle repair 24 hours following cardiotoxin-induced muscle injury, Wnt inhibitor, sFRP2 is expressed in proliferating myoblasts and there is no Wnt activity ; furthermore, administration of Wnt inhibitor, sFRP3 to single-fiber cultures at early stages of muscle repair day 2 of culture has no effect on Wnt inhibition but when sFRP3 is added at later time points day 3.
These data suggest that Wnt activity does not occur during the early proliferative stages of muscle repair Notch and Wnt orchestrate together for cell fate decisions in other systems but their roles have not been determined to be similar in the skeletal muscle model - A co-activation of Notch and Wnt promote proliferation of progenitor intestinal epithelial cells When Notch and Wnt are both active in proliferating progenitor cells within the crypt region of the small intestine, the cells continue to proliferate and form the intestinal absorptive cells called enterocytes Determining if Wnt and Notch regulate each other will aid in delineating the mechanism of orchestration between Notch and Wnt during cell fate determination including postnatal myogenesis.
Conversely, it should be noted that there is evidence suggesting Wnt signaling is upstream of Notch Furthermore, in the presence of exogenous Wnt3a and Delta1 there is increased Hes1 and Deltex1 expression in hematopoietic stem cells Identifying the location for the point of transition between Notch and Wnt signaling would be beneficial in determining the mechanism of Notch and Wnt orchestration for cell fate decisions including postnatal myogenesis.
Presenilins, which assist in cleaving full-length Notch to its activated state, have also been suggested to be major players in the coordination of the Notch and Wnt pathways These date suggest that Presenilins may function as mediator between Notch and Wnt by de-regulating Wnt signaling. The orchestration of Notch and Wnt is crucial for cell fate decisions of a variety of tissues. However, there are conflicting reports on the mechanisms of their co-regulation during regenerative processes in skeletal muscle and other tissue models.
Of particular interest, is understanding Notch and Wnt's role in satellite cell biology such as regulating myogenic proteins during postnatal myogenesis. What is even less known is the effect of different muscle injury models including physiological stimuli in regulating Notch, Wnt and myogenic protein expression during adult muscle repair. Physiological stimuli and muscle regeneration and growth The current muscle injury models for examining the roles of Notch and Wnt in satellite cell regulation during postnatal myogenesis consist primarily of artificial techniques which do not consider the influences of other biological systems and are not easily applied to muscle function scenarios.
Physiological stimuli such as contraction-induced muscle injury injurious exercise and growth models overload hypertrophy, resistance exercises are functionally relevant and involve the contribution of multiple active biological systems which are important to consider when investigating sources responsible for muscle regenerative processes. A common injurious exercise model, downhill running DHRuses eccentric muscle contractions in which the contracting muscle is forced to lengthen by an external force while producing tension 9- DHR in rodents results in decreased isometric force production and elevations in muscle injury makers such as creatine kinase activity and muscle injury criteria identified with Hematoxylin and Eosin staining, DHR is also known to stimulate muscle remodeling and myogenesis processes - Overall, there is sufficient data to exhibit that DHR induces a myogenic response and may be worthy as a model for studying postnatal myogenesis regulation.
One aspect to consider when using the DHR model to study myogenesis is that the time course of muscle repair with the DHR model may be different than with artificial muscle injury models. At hours post-CTX, muscle regeneration dominates while signs of muscle repair are not present until hours to hours post-DHR.
Notch and Wnt Signaling, Physiological Stimuli and Postnatal Myogenesis
Although DHR does not induce as profound of muscle injury as seen in the CTX model, this exercise injury model still induces a myogenic response. Besides the DHR model, other eccentric contraction models are available to study muscle regeneration - Eccentric contractions on an isokinetic dynamometer results in muscle remodeling in the hours to days post exercise including increased expression of hepatocyte growth factor HGFMyoD, mechano growth factor, neural cell adhesion molecule, Pax7 and insulin-like growth factor 1 IGF1 - In situ muscle lengthening contraction injury model is a physiological test that uses a rigorous and precise control of muscle contraction by electrically stimulating motor neurons of associated muscles of interest - With its ability to quantify muscle function this biological model offers a unique approach relative to other muscle injury protocol.
Inflammation is also present at three days post injury with reports of a 7. With the profound magnitude of muscle injury present in this physiological stimulus model as well as the presence of myogenic-associated proteins, it seems plausible that one could use this novel muscle injury model to study the regulation of myogenic repair as it relates to recovery of function.
Muscle overload techniques heavy resistance exercise, stretch hypertrophy and compensatory hypertrophy are physiological stimuli capable of investigating the contribution of myogenic properties to growth.
Overload-induced muscle hypertrophy is a type of a compensatory hypertrophy model in which muscles are ablated such as the gastrocnemius, soleus or tibialis anterior and the remaining muscles such as the plantaris or extensor digitorum longus work harder to maintain muscle function This compensation of the remaining muscles results in growth including increased DNA synthesis, muscle mass and force production - It is suggested that activation of satellite cells is a source of the new myonuclei rather than sole provision from differentiated myotubes During the early hours and within the first week of compensatory overload there is evidence of satellite cell activation and myogenic response including up-regulated Pax 7, M-Cadherin, MyoD, Desmin, Myogenin, MHC as well as fibroblast growth factors 1 and 7, IGF1 and HGF, - The contribution of satellite cells to muscle repair and growth is not conclusive.
There is evidence supporting the notion that satellite cells are critical to muscle repair, recovery of muscle function as well as important to muscle growth, - Irradiation-induced inhibition of proliferating myogenic cells results in decreased force recovery following injurious eccentric contractions to rodent anterior crural muscles In addition, MyoD and Myogenin transcripts are increased at three, seven, 14, and 21 days post lengthening contractions in non-irradiated mice while irradiated mice do not show any MRF up-regulation There is evidence of the importance of satellite cells in the overload muscle growth models In addition, there is no increase in muscle mass, myofibrillar protein, DNA content, or cross sectional area of a single myofiber at three months following overloading in irradiated rat hindlimb muscle However, it needs to be mentioned that there is data demonstrating the occurrence of muscle hypertrophy without up regulation of myogenic proteins following muscle overload and proponents that propose the critical component for muscle hypertrophy is protein synthesis and not satellite cells There is increased muscle hypertrophy in overloaded mice that over-express muscle IGF1 or Akt - In addition, irradiated mice that are introduced with viral-mediated IGF1 gene transfer have greater muscle growth than with just irradiation alone To add complication to the controversy, it is also proposed that both satellite cells and protein synthesis contribute to muscle repair and hypertrophy, Barton Davis et al.
They suggest that IGF1 could co-activate satellite cells and adult muscle fibers to induce hypertrophy so that in conditions in which irradiation depletes proliferating activated satellite cells the mature muscle fibers could be responsible for the increased protein synthesis Others suggest that the predominating mechanism of either satellite cell activation or increased protein synthesis may be due to the timeline of events following a hypertrophic stimulus More work is needed to delineate the importance of protein synthesis compared to satellite cells to muscle repair and growth.
The interaction of physiological stimuli, Notch and Wnt, and muscle regeneration There are still many questions in regards to the contribution of satellite cells to muscle repair and growth. Furthermore, studying the communication of cell signaling pathways important for muscle regeneration such as Notch, Wnt as relates to satellite cell activation will aid in delineating the source of satellite cell activation resulting in determining the importance satellite cells to muscle repair and growth.
Research on the interaction of physiological stimuli, Notch and Wnt signaling and muscle repair and growth would aid in furthering the understanding of satellite cell regulation.
Physiological stimuli up-regulates components of Notch and Wnt signaling 92, - DHR increases Notch1 and Delta1 expression in myogenic cells at 72 hours through hours post-injury A single injurious bout of resistance exercise increases Notch1 and downstream regulator Hes6 mRNA Overload-induced hypertrophy also increases Notch1 expression in Pax7-positive myogenic cells There is an abundance of evidence stating that physiological stimuli up-regulates Notch and Wnt signaling but more research is needed on the effect of physiological stimuli on the orchestration and regulation of these signaling pathways during muscle repair.
Conclusion With the development of tools available to identify satellite cells, it is feasible to study the characterization and regulation of postnatal myogenesis. More work is needed to discern the factor s responsible for re-awakening these normally quiescent skeletal muscle stem cells as well as to determine the collaboration of the various signaling mechanisms as relates to regulating the myogenic proteins. Notch and Wnt signaling have recently been identified to be critical to muscle regeneration.
The revelation of the importance of Notch and Wnt signaling to during muscle repair is recognized in artificial muscle injury models but is largely unknown in physiological stimuli models. Contracting skeletal muscle releases a plethora of signals that induces autocrine and paracrine effects that may influence the regulation of postnatal myogenesis differently than localized muscle injury models. Therefore, understanding the intrinsic and systemic response of contracting muscle will aid in deciphering the regulation of satellite cells and muscle repair as well as understanding the molecular mechanisms responsible for the beneficial protective effects of exercise to cardiovascular disease and cancer.
Conflict of Interest The author has declared that no conflict of interest exists. Satellite cell of skeletal muscle fibers. J Biophys Biochem Cytol. Conboy I, Rando TA. The regulation of notch signaling controls satellite cell activation and cell fate determination in postnatal myogenesis.
Notch-mediated restoration of regenerative potential aged muscle. Inhibition of notch signaling induces myotube hypertrophy by recruiting a subpopulation of reserve cells. Journal of Cellular Physiology. The Journal of Biological Chemistry. Inhibition of myogenesis by Notch: Hawke T, Garry DJ. Sarcomere dynamics and contraction-induced injury to maximally activate single muscle fibers from soleus muscles of rat.
Eccentric exercise-induced injuries to contractile and cytoskeletal muscle fibre components. Med Sci Sports Exerc.
Muscle impairment occurs rapidly and precedes inflammatory cell accumulation after mechanical loading. The process of new plasmalemma formation in focally injured skeletal muscle fibers.
Holterman C, Rudnicki MA. Molecular regulation of satellite cell function. Direct isolation of satellite cells for skeletal muscle regeneration.
Essential and separable roles for Syndecan-3 and Syndecan-4 in skeletal muscle development and regeneration. Syndecanexpressing muscle progenitor cells in the SP engraft as satellite cells during muscle regeneration. Self-renewal and expansion of single transplanted muscle stem cells. Shi X, Garry DJ. Muscle stem cells in development, regeneration, and disease. Expression of CD34 and Myf5 defines the majority of quiescent adult skeletal muscle satellite cells.
The Journal of Cell Biology. Wagers A, Conboy IM. Cellular and molecular signatures of muscle regeneration: Cornelison D, Wold BJ. Single-cell analysis of regulatory gene expression in quiescent and activated mouse skeletal muscle satellite cells. Purification and cell-surface marker characterization of quiescent satellite cells from murine skeletal muscle by a novel monoclonal antibody. Isolation of adult mouse myogenic progenitors: Further characterisation of the molecular signature of quiescent and activated mouse muscle satellite cells.
IL-6 and other myokines. Heat stress increases myonuclear number and fiber size via satellite cell activation in rat regenerating soleus fibers. The transition from proliferation to differentiation is delayed in satellite cells from mice lacking MyoD.
Charge S, Rudnicki MA. Cellular and molecular regulation of muscle regeneration. MyoD or Myf-5 is required for the formation of skeletal muscle. Skeletal muscle stem cells in developmental versus regenerative myogenesis. Muscle deficiency and neonatal death in mice with a targeted mutation in the myogenin gene. Myogenin gene disruption results in perinatal lethality because of severe muscle defect.
Acceleration of muscle regeneration by local injection of muscle-specific microRNAs in rat skeletal muscle injury model.
J Cell Mol Med. Muscle stem cell behavior is modified by microRNA regulation of Pax3 expression. The molecular regulation of muscle stem cell function. Relaix F, Marcelle C. Curr Opin Cell Biol. Pax7 and myogenic progression in skeletal muscle satellite cells.
Adult satellite cells and embryonic muscle progenitors have distinct genetic requirements. Muscle satellite cells are multipotential stem cells that exhibit myogenic, osteogenic, and adipogenic differentiation.
Bone morphogenetic protein-2 converts the differentiation pathway of C2C12 myoblasts into the osteoblast lineage. Recombinant human bone morphogenetic protein-2 stimulates osteoblastic maturation and inhibits myogenic differentiation in vitro.
Thiazolidinediones and fatty acids convert myogenic cells into adipose-like cells. Osteogenic induction in hereditary disorders of heterotopic ossification. Clin Orthop Relat Res. Expression of specific white adipose tissue genes in denervation-induced skeletal muscle fatty degeneration. Pastoret C, Sebille A. Inhibition of adipogenesis by Wnt signaling. Activation of an adipogenic program in adult myoblasts with age. Modulation of Rho GTPase signaling regulates a switch between adipogenesis and myogenesis.
Mechanical stretch inhibits myoblast-to-adipocyte differentiation through Wnt signaling. Biochem Biophys Res Commun.
Interleukin stimulates adiponectin secretion by 3T3-L1 adipocytes: Wnt10b deficiency promotes coexpression of myogenic and adipogenic programs in myoblasts. Identification of self-renewing myoblasts in the progeny of single human muscle satellite cells.
Dynamics of myoblast transplantation reveal a discrete minority of precursors with stem cell-like properties as the myogenic source. Cell heterogeneity upon myogenic differentiation: Stem cell function, self-renewal and behavioral heterogeneity of cells from the adult muscle satellite cell niche. Satellite cell proliferative compartments in growing skeletal muscles.
Muscle satellite cells adopt divergent fates: Olguin H, Olwin BB. Pax-7 up-regulation inhibits myogenesis and cell cycle progression in satellite cells: Pattern of Pax7 expression during myogenesis in the posthatch chicken establishes a model for satellite cell differentiation and renewal. High incidence of non-random template strand segregation and asymmetric fate determination in dividing stem cells and their progeny.
Sca-1 negatively regulates proliferation and differentiation of muscle cells. A home away from home: Morrison S, Kimble J. Asymmetric and symmetric stem-cell divisions in development and cancer. Notch signaling in the nervous system. Pieces still missing from the puzzle. Notch, a universal arbiter of cell fate decisions.
Combinatorial signaling by Sonic hedgehog and Wnt family members induces myogenic bHLH gene expression in the somite. Differential activation of Myf5 and MyoD by different Wnts in explants of mouse paraxial mesoderm and the later activation of myogenesis in the absence of Myf5. Notch signaling imposes two distinct blocks in the differentiation of C2C12 myoblasts.
Notch signaling inhibits muscle cell differentiation through a CBF1-independent pathway. Rapid Notch1 nuclear translocation after ligand binding depends on presenilin-associated gamma-secretase activity. Annals New York Academy of Sciences.
Functional notch signaling is required for BMP4-induced inhibition of myogenic differentiation. A sensitive and quantitative assay for measuring cleavage of presenilin substrates. Presenilin-1 acts via Id1 to regulate the function of muscle satellite cells in a gamma-secretase-independent manner. Premature myogenic differentiation and depletion of progenitor cells cause severe muscle hypotrophy in Delta1 mutants.
RBP-J Rbpsuh is essential to maintain muscle progenitor cells and to generate satellite cells. Alternative pre-mRNA splicing governs expression of a conserved acidic transactivation domain in myocyte enhancer factor 2 factors of striated muscle and brain. Separable regulatory elements governing myogenin transcription in mouse embryogenesis. The Notch effector Hey1 associates with myogenic target genes to repress myogenesis.
Turning it up a Notch: Cross-talk between the Notch and TGF-beta signaling pathways mediated by interaction of the Notch intracellular domain with Smad3. Two mammalian helix-loop-helix factors structurally related to Drosophila hairy and Enhancer of split.
Regulation of myogenic terminal differentiation by the hairy-related transcription factor CHF2. Skeletal muscle satellite cells and adult myogenesis. Expression of beta-catenin is necessary for physiological growth of adult skeletal muscle.