MSX2 mediates entry of human pluripotent stem cells into mesendoderm by simultaneously suppressing SOX2 and activating NODAL signaling

Thomson JA, Itskovitz-Eldor J, Shapiro SS, et al. Embryonic stem cell lines derived from human blastocysts. Science 1998; 282:1145–1147.

Yu J, Vodyanik MA, Smuga-Otto K, et al. Induced pluripotent stem cell lines derived from human somatic cells. Science 2007; 318:1917–1920.

Rossant J . Stem cells and early lineage development. Cell 2008; 132:527–531.

Yamanaka S . A fresh look at iPS cells. Cell 2009; 137:13–17.

Boyer LA, Lee TI, Cole MF, et al. Core transcriptional regulatory circuitry in human embryonic stem cells. Cell 2005; 122:947–956.

Dalton S . Signaling networks in human pluripotent stem cells. Curr Opin Cell Biol 2013; 25:241–246.

Vallier L, Mendjan S, Brown S, et al. Activin/Nodal signalling maintains pluripotency by controlling Nanog expression. Development 2009; 136:1339–1349.

James D, Levine AJ, Besser D, Hemmati-Brivanlou A . TGFbeta/activin/nodal signaling is necessary for the maintenance of pluripotency in human embryonic stem cells. Development 2005; 132:1273–1282.

Armstrong L, Hughes O, Yung S, et al. The role of PI3K/AKT, MAPK/ERK and NFkappabeta signalling in the maintenance of human embryonic stem cell pluripotency and viability highlighted by transcriptional profiling and functional analysis. Hum Mol Genet 2006; 15:1894–1913.

Zhou J, Su P, Wang L, et al. mTOR supports long-term self-renewal and suppresses mesoderm and endoderm activities of human embryonic stem cells. Proc Natl Acad Sci USA 2009; 106:7840–7845.

Singh AM, Reynolds D, Cliff T, et al. Signaling network crosstalk in human pluripotent cells: a Smad2/3-regulated switch that controls the balance between self-renewal and differentiation. Cell Stem Cell 2012; 10:312–326.

Lian X, Zhang J, Zhu K, Kamp TJ, Palecek SP . Insulin inhibits cardiac mesoderm, not mesendoderm, formation during cardiac differentiation of human pluripotent stem cells and modulation of canonical Wnt signaling can rescue this inhibition. Stem Cell 2013; 31:447–457.

Woll PS, Morris JK, Painschab MS, et al. Wnt signaling promotes hematoendothelial cell development from human embryonic stem cells. Blood 2008; 111:122–131.

Vijayaragavan K, Szabo E, Bosse M, Ramos-Mejia V, Moon RT, Bhatia M . Noncanonical Wnt signaling orchestrates early developmental events toward hematopoietic cell fate from human embryonic stem cells. Cell Stem Cell 2009; 4:248–262.

Xu RH, Chen X, Li DS, et al. BMP4 initiates human embryonic stem cell differentiation to trophoblast. Nat Biotechnol 2002; 20:1261–1264.

Zhang P, Li J, Tan Z, et al. Short-term BMP-4 treatment initiates mesoderm induction in human embryonic stem cells. Blood 2008; 111:1933–1941.

Vallier L, Alexander M, Pedersen RA . Activin/Nodal and FGF pathways cooperate to maintain pluripotency of human embryonic stem cells. J Cell Sci 2005; 118:4495–4509.

Beattie GM, Lopez AD, Bucay N, et al. Activin A maintains pluripotency of human embryonic stem cells in the absence of feeder layers. Stem Cell 2005; 23:489–495.

Ramos-Mejia V, Melen GJ, Sanchez L, et al. Nodal/Activin signaling predicts human pluripotent stem cell lines prone to differentiate toward the hematopoietic lineage. Mol Ther 2010; 18:2173–2181.

Brown S, Teo A, Pauklin S, et al. Activin/Nodal signaling controls divergent transcriptional networks in human embryonic stem cells and in endoderm progenitors. Stem Cell 2011; 29:1176–1185.

Chng Z, Teo A, Pedersen RA, Vallier L . SIP1 mediates cell-fate decisions between neuroectoderm and mesendoderm in human pluripotent stem cells. Cell Stem Cell 2010; 6:59–70.

Zhou J, Su P, Li D, Tsang S, Duan E, Wang F . High-efficiency induction of neural conversion in human ESCs and human induced pluripotent stem cells with a single chemical inhibitor of transforming growth factor beta superfamily receptors. Stem Cell 2010; 28:1741–1750.

Richter A, Valdimarsdottir L, Hrafnkelsdottir HE, et al. BMP4 promotes EMT and mesodermal commitment in human embryonic stem cells via SLUG and MSX2. Stem Cell 2014; 32:636–648.

Bell JR, Noveen A, Liu YH, et al. Genomic structure, chromosomal location, and evolution of the mouse Hox 8 gene. Genomics 1993; 17:800.

Davidson D . The function and evolution of Msx genes: pointers and paradoxes. Trends Genet 1995; 11:405–411.

MacKenzie A, Ferguson MW, Sharpe PT . Expression patterns of the homeobox gene, Hox-8, in the mouse embryo suggest a role in specifying tooth initiation and shape. Development 1992; 115:403–420.

Li Y, Liu J, Hudson M, Kim S, Hatch NE . FGF2 promotes Msx2 stimulated PC-1 expression via Frs2/MAPK signaling. J Cell Biochem 2010; 111:1346–1358.

Newberry EP, Latifi T, Battaile JT, Towler DA . Structure-function analysis of Msx2-mediated transcriptional suppression. Biochemistry 1997; 36:10451–10462.

Satokata I, Ma L, Ohshima H, et al. Msx2 deficiency in mice causes pleiotropic defects in bone growth and ectodermal organ formation. Nat Genet 2000; 24:391–395.

Ma L, Golden S, Wu L, Maxson R . The molecular basis of Boston-type craniosynostosis: the Pro148-->His mutation in the N-terminal arm of the MSX2 homeodomain stabilizes DNA binding without altering nucleotide sequence preferences. Hum Mol Genet 1996; 5:1915–1920.

Garcia-Minaur S, Mavrogiannis LA, Rannan-Eliya SV, et al. Parietal foramina with cleidocranial dysplasia is caused by mutation in MSX2. Eur J Hum Genet 2003; 11:892–895.

Jabs EW, Muller U, Li X, et al. A mutation in the homeodomain of the human MSX2 gene in a family affected with autosomal dominant craniosynostosis. Cell 1993; 75:443–450.

Wuyts W, Reardon W, Preis S, et al. Identification of mutations in the MSX2 homeobox gene in families affected with foramina parietalia permagna. Hum Mol Genet 2000; 9:1251–1255.

Quinn LM, Latham SE, Kalionis B . The homeobox genes MSX2 and MOX2 are candidates for regulating epithelial-mesenchymal cell interactions in the human placenta. Placenta 2000; 21 Suppl A:S50–54.

di Bari MG, Ginsburg E, Plant J, Strizzi L, Salomon DS, Vonderhaar BK . Msx2 induces epithelial-mesenchymal transition in mouse mammary epithelial cells through upregulation of Cripto-1. J Cell Physiol 2009; 219:659–666.

Friedmann Y, Daniel CW . Regulated expression of homeobox genes Msx-1 and Msx-2 in mouse mammary gland development suggests a role in hormone action and epithelial-stromal interactions. Dev Biol 1996; 177:347–355.

Xia X, Ayala M, Thiede BR, Zhang SC . In vitro- and in vivo-induced transgene expression in human embryonic stem cells and derivatives. Stem Cells 2008; 26:525–533.

Suzuki A, Ueno N, Hemmati-Brivanlou A . Xenopus msx1 mediates epidermal induction and neural inhibition by BMP4. Development 1997; 124:3037–3044.

Bei M, Maas R . FGFs and BMP4 induce both Msx1-independent and Msx1-dependent signaling pathways in early tooth development. Development 1998; 125:4325–4333.

Evseenko D, Zhu Y, Schenke-Layland K, et al. Mapping the first stages of mesoderm commitment during differentiation of human embryonic stem cells. Proc Natl Acad Sci USA 2010; 107:13742–13747.

Mendjan S, Mascetti VL, Ortmann D, et al. NANOG and CDX2 pattern distinct subtypes of human mesoderm during exit from pluripotency. Cell Stem Cell 2014; 15:310–325.

Yu P, Pan G, Yu J, Thomson JA . FGF2 sustains NANOG and switches the outcome of BMP4-induced human embryonic stem cell differentiation. Cell Stem Cell 2011; 8:326–334.

Ran FA, Hsu PD, Wright J, Agarwala V, Scott DA, Zhang F . Genome engineering using the CRISPR-Cas9 system. Nat Protoc 2013; 8:2281–2308.

Fu H, Ishii M, Gu Y, Maxson R . Conditional alleles of Msx1 and Msx2. Genesis 2007; 45:477–481.

Nieminen P, Arte S, Pirinen S, Peltonen L, Thesleff I . Gene defect in hypodontia: exclusion of MSX1 and MSX2 as candidate genes. Hum Genet 1995; 96:305–308.

Vieux-Rochas M, Bouhali K, Mantero S, et al. BMP-mediated functional cooperation between Dlx5;Dlx6 and Msx1;Msx2 during mammalian limb development. PLoS One 2013; 8:e51700.

Qadir AS, Lee HL, Baek KH, et al. Msx2 is required for TNF-alpha-induced canonical Wnt signaling in 3T3-L1 preadipocytes. Biochem Biophys Res Commun 2011; 408:399–404.

Bernardo AS, Faial T, Gardner L, et al. BRACHYURY and CDX2 mediate BMP-induced differentiation of human and mouse pluripotent stem cells into embryonic and extraembryonic lineages. Cell Stem Cell 2011; 9:144–155.

Brugger SM, Merrill AE, Torres-Vazquez J, et al. A phylogenetically conserved cis-regulatory module in the Msx2 promoter is sufficient for BMP-dependent transcription in murine and Drosophila embryos. Development 2004; 131:5153–5165.

Sun J, Ishii M, Ting MC, Maxson R . Foxc1 controls the growth of the murine frontal bone rudiment by direct regulation of a Bmp response threshold of Msx2. Development 2013; 140:1034–1044.

Hussein SM, Duff EK, Sirard C . Smad4 and beta-catenin co-activators functionally interact with lymphoid-enhancing factor to regulate graded expression of Msx2. J Biol Chem 2003; 278:48805–48814.

Fong H, Hohenstein KA, Donovan PJ . Regulation of self-renewal and pluripotency by Sox2 in human embryonic stem cells. Stem Cell 2008; 26:1931–1938.

Graham V, Khudyakov J, Ellis P, Pevny L . SOX2 functions to maintain neural progenitor identity. Neuron 2003; 39:749–765.

Wang Z, Oron E, Nelson B, Razis S, Ivanova N . Distinct lineage specification roles for NANOG, OCT4, and SOX2 in human embryonic stem cells. Cell Stem Cell 2012; 10:440–454.

Lin IY, Chiu FL, Yeang CH, et al. Suppression of the SOX2 neural effector gene by PRDM1 promotes human germ cell fate in embryonic stem cells. Stem Cell Rep 2014; 2:189–204.

Lengler J, Bittner T, Munster D, Gawad Ael D, Graw J . Agonistic and antagonistic action of AP2, Msx2, Pax6, Prox1 AND Six3 in the regulation of Sox2 expression. Ophthalmic Res 2005; 37:301–309.

Tomioka M, Nishimoto M, Miyagi S, et al. Identification of Sox-2 regulatory region which is under the control of Oct-3/4-Sox-2 complex. Nucleic Acids Res 2002; 30:3202–3213.

Twizere JC, Lefebvre L, Collete D, et al. The homeobox protein MSX2 interacts with tax oncoproteins and represses their transactivation activity. J Biol Chem 2005; 280:29804–29811.

Yoon WJ, Cho YD, Cho KH, et al. The Boston-type craniosynostosis mutation MSX2 (P148H) results in enhanced susceptibility of MSX2 to ubiquitin-dependent degradation. J Biol Chem 2008; 283:32751–32761.

Arnold SJ, Robertson EJ . Making a commitment: cell lineage allocation and axis patterning in the early mouse embryo. Nat Rev Mol Cell Biol 2009; 10:91–103.

Schier AF, Shen MM . Nodal signalling in vertebrate development. Nature 2000; 403:385–389.

Sumi T, Tsuneyoshi N, Nakatsuji N, Suemori H . Defining early lineage specification of human embryonic stem cells by the orchestrated balance of canonical Wnt/beta-catenin, Activin/Nodal and BMP signaling. Development 2008; 135:2969–2979.

Lallemand Y, Nicola MA, Ramos C, Bach A, Cloment CS, Robert B . Analysis of Msx1; Msx2 double mutants reveals multiple roles for Msx genes in limb development. Development 2005; 132:3003–3014.

Zhang X, Huang CT, Chen J, et al. Pax6 is a human neuroectoderm cell fate determinant. Cell Stem Cell 2010; 7:90–100.

Suwinska A, Czolowska R, Ozdzenski W, Tarkowski AK . Blastomeres of the mouse embryo lose totipotency after the fifth cleavage division: expression of Cdx2 and Oct4 and developmental potential of inner and outer blastomeres of 16- and 32-cell embryos. Dev Biol 2008; 322:133–144.

Bessonnard S, De Mot L, Gonze D, et al. Gata6, Nanog and Erk signaling control cell fate in the inner cell mass through a tristable regulatory network. Development 2014; 141:3637–3648.