Wnt Signaling Regulates the Function of MyoD and Myogenin

The myogenic regulatory factors (MRFs), MyoD and myogenin, can induce myogenesis in a variety of cell lines but not efficiently in monolayer cultures of P19 embryonal carcinoma stem cells. Aggregation of cells expressing MRFs, termed P19[MRF] cells, results in an approximately 30-fold enhancement of myogenesis. Here we examine molecular events occurring during P19 cell aggregation to identify potential mechanisms regulating MRF activity. Although myogenin protein was continually present in the nuclei of >90% of P19[myogenin] cells, only a fraction of these cells differentiated. Consequently, it appears that post-translational regulation controls myogenin activity in a cell lineage-specific manner. A correlation was obtained between the expression of factors involved in somite patterning, including Wnt3a, Wnt5b, BMP-2/4, and Pax3, and the induction of myogenesis. Co-culturing P19[Wnt3a] cells with P19[MRF] cells in monolayer resulted in a 5- to 8-fold increase in myogenesis. Neither BMP-4 nor Pax3 was efficient in enhancing MRF activity in unaggregated P19 cultures. Furthermore, BMP-4 abrogated the enhanced myogenesis induced by Wnt signaling. Consequently, signaling events resulting from Wnt3a expression but not BMP-4 signaling or Pax3 expression, regulate MRF function. Therefore, the P19 cell culture system can be used to study the link between somite patterning events and myogenesis. The myogenic regulatory factors (MRFs), MyoD and myogenin, can induce myogenesis in a variety of cell lines but not efficiently in monolayer cultures of P19 embryonal carcinoma stem cells. Aggregation of cells expressing MRFs, termed P19[MRF] cells, results in an approximately 30-fold enhancement of myogenesis. Here we examine molecular events occurring during P19 cell aggregation to identify potential mechanisms regulating MRF activity. Although myogenin protein was continually present in the nuclei of >90% of P19[myogenin] cells, only a fraction of these cells differentiated. Consequently, it appears that post-translational regulation controls myogenin activity in a cell lineage-specific manner. A correlation was obtained between the expression of factors involved in somite patterning, including Wnt3a, Wnt5b, BMP-2/4, and Pax3, and the induction of myogenesis. Co-culturing P19[Wnt3a] cells with P19[MRF] cells in monolayer resulted in a 5- to 8-fold increase in myogenesis. Neither BMP-4 nor Pax3 was efficient in enhancing MRF activity in unaggregated P19 cultures. Furthermore, BMP-4 abrogated the enhanced myogenesis induced by Wnt signaling. Consequently, signaling events resulting from Wnt3a expression but not BMP-4 signaling or Pax3 expression, regulate MRF function. Therefore, the P19 cell culture system can be used to study the link between somite patterning events and myogenesis. myogenic regulatory factor Sonic Hedgehog signaling molecule Frizzled 1 receptor myocyte enhancer factor 2C lymphoid-enhancer factor 1 T-cell factor bone morphogenic protein kilobase(s) MyHC, myosin heavy chain A family of myogenic basic helix-loop-helix transcription factors (MRFs)1 plays a major role in controlling the events leading to skeletal muscle development (1Molkentin J.D. Olson E.N. Curr. Opin. Genet. Dev. 1996; 6: 445-453Crossref PubMed Scopus (391) Google Scholar, 2Yun K. Wold B. Curr. Opin. Cell Biol. 1996; 8: 877-889Crossref PubMed Scopus (326) Google Scholar). These transcription factors, MyoD, myf-5, myogenin, and myf-6/MRF-4/herculin (3Davis R.L. Weintraub H. Lassar A.B. Cell. 1987; 51: 987-1000Abstract Full Text PDF PubMed Scopus (2514) Google Scholar, 4Braun T. Buschhausen-Denker G. Bober E. Tannich E. Arnold H.H. 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Google Scholar). of cells that MyoD protein present and of binding and aggregation C. K. McBurney M.W. Cell Res. 1999; PubMed Scopus (24) Google Scholar). that aggregation signaling that regulate MyoD aggregation MyoD by the expression of an or by muscle-specific that myogenin, MyoD, aggregation to myogenesis S. Skerjanc I.S. J. Biol. Chem. 2000; 275: Full Text Full Text PDF PubMed Scopus Google Scholar). In the present we potential mechanisms involved in regulating MRF activity during Here we that myogenin activity appears to be in a cell lineage-specific and post-translational manner. During factors such as Wnt3a, BMP-2/4, and Pax3 are In monolayer Wnt3a, but not Pax3 or can induced myogenesis in P19 cells, the in expression are by the McBurney M.W. 1987; PubMed Scopus Google Scholar). The a the of MyoD (3Davis R.L. Weintraub H. Lassar A.B. Cell. 1987; 51: 987-1000Abstract Full Text PDF PubMed Scopus (2514) Google Scholar), as G. K. McBurney M.W. Mol. Cell. Biol. 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To P19 cell with of 1 of 1 of and of To cells expressing MyoD and myogenin, with of of 1 of 1 of and of on one to and cells in a and expressing MyoD, myogenin, and MyoD and myogenin are termed I.S. McBurney M.W. Mol. Cell. Biol. 1994; Scopus Google Scholar), S. Skerjanc I.S. J. Biol. Chem. 2000; 275: Full Text Full Text PDF PubMed Scopus Google Scholar), and was induced by P19 or cells or The or of on the of the MRFs to induce skeletal myogenesis. only in the of cells muscle on and skeletal muscle on as and in tissue culture and or the In the aggregation cells and 1 tissue culture To the of Pax3 expression on the activity of MyoD or myogenin, was and cell of and 1 of and cells the system to the cells and to in monolayer and on To cells that MyoD and Pax3, cells with of 1 of 1 of and of the C. H. Mol. Cell. Biol. 1987; 7: PubMed Scopus Google Scholar). to be and in and expressing MyoD and Pax3 as To the of BMP-4 on the of MyoD and myogenin to induce and cells in monolayer and in the and of and BMP-4 and or in monolayer culture or of To the of Wnt3a on MRF P19[MRF] cells with P19[Wnt3a] cells in of or on the A of cells was in These in the of BMP-4 in or in and with the muscle myosin of a D. T. D.A. J. Cell Biol. PubMed Scopus Google Scholar), was 1 myogenin of the W.E. K. Dev. Genet. 1996; PubMed Scopus Google Scholar), and was in cells 1 in of with 1 of in a of and was with a and with a and and with a with P19 cell lines and cell was from P19 and cell cultures by the and C. J. PubMed Scopus Google Scholar). was as I.S. McBurney M.W. Mol. Cell. Biol. 1994; Scopus Google Scholar). was on a to by and was by The was to to with a The on a of and was in and in was by and with a from was from The used a from the M.A. G. McBurney M.W. Dev. 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Chem. 2000; 275: Full Text Full Text PDF PubMed Scopus Google Scholar). To examine the expression of MyoD and myogenin the cell lines that to cells I.S. McBurney M.W. Mol. Cell. Biol. 1994; Scopus Google and cells S. Skerjanc I.S. J. Biol. Chem. 2000; 275: Full Text Full Text PDF PubMed Scopus Google Scholar), cell lines not of as a as by with the not of aggregation with or and E cells and on P19 cells not skeletal muscle with 1 or 1 on P19 cells muscle in the of 1 as M.A. McBurney M.W. and A Scholar). Consequently, the activity of myogenin or in with MyoD, was by myogenin was present in P19 stem cells on aggregation S. Skerjanc I.S. J. Biol. Chem. 2000; 275: Full Text Full Text PDF PubMed Scopus Google Scholar), the of myogenin to in monolayer that the myogenin protein was not present or not that regulation myogenin protein from To examine with an was on and P19 cells and aggregation protein and was present in the nuclei and of cells and and In cell lines myogenin was found to be present in >90% of the nuclei by cells on from of cell A that myogenin protein was present in the with the of the nuclei to a of the by the of myogenin P19 cells not myogenin protein and A and or myogenin protein present in the of cells a form of post-translational regulation the activity of the of the cells skeletal only of the nuclei by cells on from of cell that the potential post-translational regulation of myogenin during the of P19 cells be cell Consequently, only a of the cells the myogenin activity. that a of cells that factors involved in regulating MRF activity. To the of skeletal a of aggregation was and cells. in the of and 1 tissue culture expression to the of myogenesis and the results by skeletal myogenesis of with an enhancement of myogenesis in the of to These results that factors to the MRFs be between and of To identify that be involved in regulating MyoD and myogenin a of skeletal muscle development was in and cells The expression of factors involved in somite patterning, such as and and and Pax3, by The results obtained and not cells found to be with P19 cells MyoD was the from to in cells and not in the cell The skeletal muscle-specific was aggregation on and on in cells expressing The mesoderm was on in P19 and cells the induction of as G. K. McBurney M.W. 1994; Google Scholar). of in P19 cells not to any of these cells. was from on and and was in the cells that aggregation Wnt3a was from on and expression was or during the not The expression of and BMP-4 on and and Pax3 expression on Therefore, the expression of factors involved in somite patterning was by aggregation of and cells the to these factors regulating MRF activity. A of skeletal myogenesis was the expression of factors to be present during myogenesis. P19 cells in the of enhanced the of skeletal and the of S. Skerjanc I.S. In Cell. Dev. Biol. 1999; PubMed Scopus Google Scholar). on from during the P19 cells in on 1 was from 1 on Wnt3a was the factor from and was not during the not BMP-4 was from and Pax3 from The of the expression of of these factors to their expression in the in that the expression of these factors during myogenesis in a manner. During the MEF2 and MRF family to with the MRF family of factors J.D. Black B.L. Martin J.F. Olson E.N. Cell. 1995; 83: 1125-1136Abstract Full Text PDF PubMed Scopus (708) Google Scholar), was from The MRFs, MyoD and myogenin, from and to the that myogenin was in a post-translational and cell in cells and that was an expression factors during aggregation in and skeletal myogenesis and we that a during aggregation be involved in regulating the activity of the of the To of cells with of P19[Wnt3a] cells and P19 cells in the and of BMP-4 cells with P19 cell lines a of cells the was in the of BMP-4 increase in the of cells was cultures with P19[Wnt3a] cells, an increase in the of present The transcription factor Pax3 was during myogenesis and The that Pax3 or regulate MRF activity was by expressing Pax3 in and cell these cells and in monolayer increase in the of cells Pax3 expression not The of Pax3 in MRF activation was by expressing Pax3 in cells. increase in myogenesis in these cell lines in monolayer or to induce myogenesis not To results in the of cells present on a and the results of these are in a The of cells the of cells in cultures and cultures 8-fold The of cells in cells by and in cells by in the of BMP-4 Furthermore, the of BMP-4 in of P19[MRF] cells and P19[Wnt3a] cells Wnt3a activation of MyoD and myogenin function In and cell lines in the of of BMP-4 and not in the of skeletal not These that Wnt3a expression but not Pax3 or can to an activation of MRF function in P19 cells. Furthermore, expression can the of Wnt to induce MRF function. The mechanisms involved in the activation of MRF function during aggregation of P19 cells or in with MyoD, was to induce of myogenesis in P19 cells in the of protein was found in the nuclei of >90% of P19 cells and and only a fraction of these cells skeletal Therefore, myogenin activity appears to be in a cell lineage-specific and post-translational in cells. A correlation was obtained between the activation of MRF function and the expression of somite patterning factors, such as Wnt3a, Wnt5b, BMP-2/4, and Pax3, during was found that Wnt3a the to the MRFs the the conversion of stem cells skeletal efficient with Neither Pax3 nor BMP-4 was able to on the BMP-4 the of Wnt to the Therefore, Wnt signaling events regulate MRF and signaling can be by signaling. The of expression of factors in P19 cells the in Wnt and in the neural and a of events that results in the to the expression of the MRFs, a Pax3 Hauschka S.D. 1995; Google Scholar, S. Borello U. E. R. J. D. M. Cossu G. 1998; PubMed Google Scholar, C. M. 1997; PubMed Google Scholar, R. M. Lassar A.B. Genes Dev. 1998; PubMed Scopus Google Scholar, S. D. Cossu G. M. Cell. 1997; Full Text Full Text PDF PubMed Scopus Google Scholar, M. R. S. M. Lassar A.B. Cell. 1997; Full Text Full Text PDF PubMed Scopus Google Scholar, H. B. K. 1999; Google Scholar). result to that the of events by Wnt signaling regulating MRF activity in addition to regulating MRF The that in the neural as as in the mesoderm function to the MRFs during myogenesis in the Wnt3a and to be the Wnt family during P19 cell Wnt3a in the neural H. R. Genes Dev. PubMed Scopus Google Scholar). in the and during S. M.J. G. Genes Dev. 1994; 8: PubMed Scopus Google Scholar, M. 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