TGF-β Family Signaling in Early Vertebrate Development

Abstract

TGF-β family ligands function in inducing and patterning many tissues of the early vertebrate embryonic body plan. Nodal signaling is essential for the specification of mesendodermal tissues and the concurrent cellular movements of gastrulation. Bone morphogenetic protein (BMP) signaling patterns tissues along the dorsal-ventral axis and simultaneously directs the cell movements of convergence and extension. After gastrulation, a second wave of Nodal signaling breaks the symmetry between the left and right sides of the embryo. During these processes, elaborate regulatory feedback between TGF-β ligands and their antagonists direct the proper specification and patterning of embryonic tissues. In this review, we summarize the current knowledge of the function and regulation of TGF-β family signaling in these processes. Although we cover principles that are involved in the development of all vertebrate embryos, we focus specifically on three popular model organisms: the mouse Mus musculus, the African clawed frog of the genus Xenopus, and the zebrafish Danio rerio, highlighting the similarities and differences between these species.

Figure 1.

TGF-β family signaling gradients during gastrulation. (A) Embryonic tissues patterned by Nodal signaling during gastrulation in mouse, Xenopus, and zebrafish. (B) The bone morphogenetic protein (BMP) signaling gradient during gastrulation. (C) The Nodal signaling gradient during gastrulation.

Figure 2.

Morphogenetic movements of mouse tissues at the onset of gastrulation. (A) NODAL signaling specifies the anterior visceral endoderm (AVE) before gastrulation. (B) The AVE migrates anteriorly as the primitive streak forms. (C) Mesendodermal cells ingress from the primitive streak and intercalate with extraembryonic tissues during gastrulation.

Figure 3.

Regulation of TGF-β family expression during axis patterning. Gene activation and repression in (A) early blastula (sphere to shield stage) and (B) the gastrula (after shield stage). Direct activators and repressors are marked by black lines. Indirect activators and repressors, and activators and repressors without sufficient evidence to prove a direct relationship, are marked by gray lines. Genes are color coded by their expression domains. References providing evidence for each relationship or expression domain are listed on the line connecting two genes or in the box with the gene name. Chd, Chordin; Dact2, Dapper homolog 2; Gsc, Goosecoid; Nog, Noggin; Spry, Sprouty. Numbers 1–91 in panels A and B refer to the following references: 1, Bassett et al. 2014; 2, Chamorro et al. 2005; 3, Chen and Schier 2002; 4, Chen and Shen 2004; 5, Cheng et al. 2004; 6, Cheyette et al. 2002; 7, Choi et al. 2007; 8, Dal-Pra et al. 2006; 9, Dougan 2003); 10, Erter et al. 2001; 11, Feldman et al. 1998; 12, Feldman et al. 2002; 13, Flores et al. 2008; 14, Furthauer et al. 2001; 15, Furthauer et al. 2002; 16, Furthauer et al. 2004; 17, Gilardelli et al. 2004; 18, Gore et al. 2005; 19, Gritsman et al. 1999; 20, Gritsman et al. 2000; 21, Hammerschmidt et al. 1996a; 22, Hashimoto et al. 2000; 23, Imai et al. 2001; 24, Joore et al. 1996; 25, Kawahara et al. 2000b; 26, Kawahara et al. 2000a; 27, Kelley et al. 2000; 28, Khan et al. 2012; 29, Kim et al. 2000; 30, Koos and Ho 1999; 31, Kovalenko et al. 2006; 32, Kuo et al. 2013; 33, Lekven et al. 2001; 34, Lele et al. 2001; 35, Leung 2003; 36, Lippok et al. 2014; 37, Lu et al. 2011; 38, Maegawa et al. 2006; 39, Melby et al. 2000; 40, Meno et al. 1999; 41, Miller-Bertoglio et al. 1997; 42, Moreno-Ayala et al. 2015; 43, Nojima et al. 2004; 44, Nguyen et al. 1998; 45, Onichtchouk et al. 2010 46, Pelegri and Maischein 1998; 47, Peng and Westerfield 2006; 48, Pezeron et al. 2006 49, Ramel and Hill 2013; 50, Ramel and Lekven 2004; 51, Ramel et al. 2005; 52, Reim and Brand 2006; 53, Reim et al. 2004; 54, Ro and Dawid 2009; 55, Ro and Dawid 2010; 56, Schneider et al. 1996; 57, Schmid et al. 2000; 58, Seiliez et al. 2006; 59, Shimizu et al. 2000; 60, Shimizu et al. 2002; 61, Shinya et al. 2000; 62, Sirotkin et al. 2000; 63, Solnica-Krezel and Driever 2001; 64, Su et al. 2007; 65, Takeda et al. 1994; 66, Tendeng and Houart 2006; 67, Tsang et al. 2000; 68, Tsang et al. 2002; 69, Tucker et al. 2008; 70, van Boxtel et al. 2015; 71, Varga et al. 2007; 72, Waxman et al. 2004; 73, Waxman 2005; 74, Willot et al. 2002; 75, Xue et al. 2014; 76, Zhang et al. 2004; 77, Belting et al. 2011; 78, Hild et al. 1999; 79, Schulte-Merker et al. 1997; 80, Xie and Fisher 2005; 81, Wang et al. 2013; 82, Xue et al. 2014; 83, Branam et al. 2010; 84, Sidi et al. 2003; 85, Connors et al. 1999; 86, Leyns et al. 1997; 87, Yamanaka et al. 1998; 88, Ryu et al. 2001; 89, Dickmeis et al. 2001; 90, Fekany-Lee et al. 2000; 91, Kapp et al. 2013.

Figure 3.

Regulation of TGF-β family expression during axis patterning. Gene activation and repression in (A) early blastula (sphere to shield stage) and (B) the gastrula (after shield stage). Direct activators and repressors are marked by black lines. Indirect activators and repressors, and activators and repressors without sufficient evidence to prove a direct relationship, are marked by gray lines. Genes are color coded by their expression domains. References providing evidence for each relationship or expression domain are listed on the line connecting two genes or in the box with the gene name. Chd, Chordin; Dact2, Dapper homolog 2; Gsc, Goosecoid; Nog, Noggin; Spry, Sprouty. Numbers 1–91 in panels A and B refer to the following references: 1, Bassett et al. 2014; 2, Chamorro et al. 2005; 3, Chen and Schier 2002; 4, Chen and Shen 2004; 5, Cheng et al. 2004; 6, Cheyette et al. 2002; 7, Choi et al. 2007; 8, Dal-Pra et al. 2006; 9, Dougan 2003); 10, Erter et al. 2001; 11, Feldman et al. 1998; 12, Feldman et al. 2002; 13, Flores et al. 2008; 14, Furthauer et al. 2001; 15, Furthauer et al. 2002; 16, Furthauer et al. 2004; 17, Gilardelli et al. 2004; 18, Gore et al. 2005; 19, Gritsman et al. 1999; 20, Gritsman et al. 2000; 21, Hammerschmidt et al. 1996a; 22, Hashimoto et al. 2000; 23, Imai et al. 2001; 24, Joore et al. 1996; 25, Kawahara et al. 2000b; 26, Kawahara et al. 2000a; 27, Kelley et al. 2000; 28, Khan et al. 2012; 29, Kim et al. 2000; 30, Koos and Ho 1999; 31, Kovalenko et al. 2006; 32, Kuo et al. 2013; 33, Lekven et al. 2001; 34, Lele et al. 2001; 35, Leung 2003; 36, Lippok et al. 2014; 37, Lu et al. 2011; 38, Maegawa et al. 2006; 39, Melby et al. 2000; 40, Meno et al. 1999; 41, Miller-Bertoglio et al. 1997; 42, Moreno-Ayala et al. 2015; 43, Nojima et al. 2004; 44, Nguyen et al. 1998; 45, Onichtchouk et al. 2010 46, Pelegri and Maischein 1998; 47, Peng and Westerfield 2006; 48, Pezeron et al. 2006 49, Ramel and Hill 2013; 50, Ramel and Lekven 2004; 51, Ramel et al. 2005; 52, Reim and Brand 2006; 53, Reim et al. 2004; 54, Ro and Dawid 2009; 55, Ro and Dawid 2010; 56, Schneider et al. 1996; 57, Schmid et al. 2000; 58, Seiliez et al. 2006; 59, Shimizu et al. 2000; 60, Shimizu et al. 2002; 61, Shinya et al. 2000; 62, Sirotkin et al. 2000; 63, Solnica-Krezel and Driever 2001; 64, Su et al. 2007; 65, Takeda et al. 1994; 66, Tendeng and Houart 2006; 67, Tsang et al. 2000; 68, Tsang et al. 2002; 69, Tucker et al. 2008; 70, van Boxtel et al. 2015; 71, Varga et al. 2007; 72, Waxman et al. 2004; 73, Waxman 2005; 74, Willot et al. 2002; 75, Xue et al. 2014; 76, Zhang et al. 2004; 77, Belting et al. 2011; 78, Hild et al. 1999; 79, Schulte-Merker et al. 1997; 80, Xie and Fisher 2005; 81, Wang et al. 2013; 82, Xue et al. 2014; 83, Branam et al. 2010; 84, Sidi et al. 2003; 85, Connors et al. 1999; 86, Leyns et al. 1997; 87, Yamanaka et al. 1998; 88, Ryu et al. 2001; 89, Dickmeis et al. 2001; 90, Fekany-Lee et al. 2000; 91, Kapp et al. 2013.

Figure 4.

Regulation of TGF-β family expression during axis patterning in Xenopus. Gene activation and repression in the early blastula (A) and gastrula (B). Direct activators and repressors are marked by black lines. Indirect activators and repressors, and activators and repressors without sufficient evidence to prove a direct relationship are marked by gray lines. Genes are color coded by their expression domains. References providing evidence for each relationship or expression domain are listed on the line connecting two genes or in the box with the gene name. Chd, Chordin; Dpr1, Dapper1; Ecto, Ectodermin; Fst, Follistatin; Gsc, Goosecoid; Nog, Noggin. Numbers 1 through 92 in panels A and B refer to the following references: 1, Agius et al. 2000; 2, Bae et al. 2011; 3, Branney et al. 2009; 4, Carnac et al. 1996; 5, Cha et al. 2008; 6, Cheyette et al. 2002; 7, Chiu et al. 2014; 8, de Almeida et al. 2008; 9, Dupont et al. 2005; 10, Eimon and Harland 1999; 11, Fletcher and Harland 2008; 12, Galli et al. 2003; 13, Glavic et al. 2001; 14, Gómez-Skarmeta et al. 2001; 15, Hashimoto-Partyka et al. 2003; 16, Hemmati-Brivanlou and Thomsen 1995; Hikasa et al. 2010; 17, Hoppler and Moon 1998; 18, Houston et al. 2002; 19, Houston 2012; 20, Karaulanov et al. 2004; 21, Katada et al. 2002; 22, Knochel et al. 2001; 23, Kurata et al. 2000; 24, Kuroda et al. 2004; 25, Laurent and Cho 1999; 26, Lea et al. 2009; 27, Li et al. 2015; 28, Marom et al. 1999; 29, Marom et al. 2005; 30, Martello et al. 2007; 31, Mochizuki et al. 2000; 32, Murakami et al. 2003; 33, Onichtchouk et al. 1996; 34, Onichtchouk et al. 1996; 35, Paulsen et al. 2011; 36, Reid et al. 2012; 37, Reversade and De Robertis 2005; 38, Reversade et al. 2005; 39, Rex et al. 2002; 40, Rosa et al. 2009; 41, Schneider et al. 1996; 42, Schohl and Fagotto 2003; 43, Schuler-Metz et al. 2000; 44, Sekiya et al. 2004; 45, Shieh et al. 2014; 46, Schmidt et al. 1995; 47, Sudou et al. 2012; 48, Takahashi et al. 2000; 49, Takeda et al. 2000; 50, Tanegashima et al. 2004; 51, Tao et al. 2005; 53, Trindade et al. 1999; 54, Vonica and Gumbiner 2007; 55, Wessely et al. 2001; 56, Witta and Sato 1997; 57, Xanthos et al. 2002; 58, Yamamoto et al. 2000; 59, Cho et al. 2013; 60, Plouhinec et al. 2013; 61, Maeda et al. 1997; 62, Onitsuka et al. 2000; 63, Suzuki et al. 1997; 64, Yamamoto et al. 2001; 65, Chiu et al. 2014; 66, Onuma et al. 2002; 67, Leyns et al. 1997; 68, Wills and Baker 2015; 69, Branford and Yost 2002; 70, Cheng et al. 2000; 71, Ohkawara 2003; 72, Glinka et al. 1998; 73, Chamorro et al. 2005; 74, Sander et al. 2007; 75, Nakamura et al. 2016; 76, Khokha et al. 2005; 77, Watanabe et al. 2003; 78, Rebbert and Dawid 1997; 79, Collart et al. 2005; 80, Piccolo et al. 1999; 81, Piccolo et al. 1996; 82, Zimmerman et al. 1996; 83, Schmidt et al. 1995; 84, Kofron et al. 1999; 85, Delaune et al. 2005; 86, Hyde and Old 2000; 87, Dickmeis et al. 2001; 88, Gawantka et al. 1995; 89, Hata et al. 2000; 90, Henningfeld et al. 2002; 91, Lee et al. 2002; 92, Lee et al. 2011a.

Figure 4.

Regulation of TGF-β family expression during axis patterning in Xenopus. Gene activation and repression in the early blastula (A) and gastrula (B). Direct activators and repressors are marked by black lines. Indirect activators and repressors, and activators and repressors without sufficient evidence to prove a direct relationship are marked by gray lines. Genes are color coded by their expression domains. References providing evidence for each relationship or expression domain are listed on the line connecting two genes or in the box with the gene name. Chd, Chordin; Dpr1, Dapper1; Ecto, Ectodermin; Fst, Follistatin; Gsc, Goosecoid; Nog, Noggin. Numbers 1 through 92 in panels A and B refer to the following references: 1, Agius et al. 2000; 2, Bae et al. 2011; 3, Branney et al. 2009; 4, Carnac et al. 1996; 5, Cha et al. 2008; 6, Cheyette et al. 2002; 7, Chiu et al. 2014; 8, de Almeida et al. 2008; 9, Dupont et al. 2005; 10, Eimon and Harland 1999; 11, Fletcher and Harland 2008; 12, Galli et al. 2003; 13, Glavic et al. 2001; 14, Gómez-Skarmeta et al. 2001; 15, Hashimoto-Partyka et al. 2003; 16, Hemmati-Brivanlou and Thomsen 1995; Hikasa et al. 2010; 17, Hoppler and Moon 1998; 18, Houston et al. 2002; 19, Houston 2012; 20, Karaulanov et al. 2004; 21, Katada et al. 2002; 22, Knochel et al. 2001; 23, Kurata et al. 2000; 24, Kuroda et al. 2004; 25, Laurent and Cho 1999; 26, Lea et al. 2009; 27, Li et al. 2015; 28, Marom et al. 1999; 29, Marom et al. 2005; 30, Martello et al. 2007; 31, Mochizuki et al. 2000; 32, Murakami et al. 2003; 33, Onichtchouk et al. 1996; 34, Onichtchouk et al. 1996; 35, Paulsen et al. 2011; 36, Reid et al. 2012; 37, Reversade and De Robertis 2005; 38, Reversade et al. 2005; 39, Rex et al. 2002; 40, Rosa et al. 2009; 41, Schneider et al. 1996; 42, Schohl and Fagotto 2003; 43, Schuler-Metz et al. 2000; 44, Sekiya et al. 2004; 45, Shieh et al. 2014; 46, Schmidt et al. 1995; 47, Sudou et al. 2012; 48, Takahashi et al. 2000; 49, Takeda et al. 2000; 50, Tanegashima et al. 2004; 51, Tao et al. 2005; 53, Trindade et al. 1999; 54, Vonica and Gumbiner 2007; 55, Wessely et al. 2001; 56, Witta and Sato 1997; 57, Xanthos et al. 2002; 58, Yamamoto et al. 2000; 59, Cho et al. 2013; 60, Plouhinec et al. 2013; 61, Maeda et al. 1997; 62, Onitsuka et al. 2000; 63, Suzuki et al. 1997; 64, Yamamoto et al. 2001; 65, Chiu et al. 2014; 66, Onuma et al. 2002; 67, Leyns et al. 1997; 68, Wills and Baker 2015; 69, Branford and Yost 2002; 70, Cheng et al. 2000; 71, Ohkawara 2003; 72, Glinka et al. 1998; 73, Chamorro et al. 2005; 74, Sander et al. 2007; 75, Nakamura et al. 2016; 76, Khokha et al. 2005; 77, Watanabe et al. 2003; 78, Rebbert and Dawid 1997; 79, Collart et al. 2005; 80, Piccolo et al. 1999; 81, Piccolo et al. 1996; 82, Zimmerman et al. 1996; 83, Schmidt et al. 1995; 84, Kofron et al. 1999; 85, Delaune et al. 2005; 86, Hyde and Old 2000; 87, Dickmeis et al. 2001; 88, Gawantka et al. 1995; 89, Hata et al. 2000; 90, Henningfeld et al. 2002; 91, Lee et al. 2002; 92, Lee et al. 2011a.

Figure 5.

Expression of Nodal pathway components during symmetry breaking and patterning of the left–right (LR) axis in a generic vertebrate embryo. (A) Physical structures involved in LR patterning or proximal to the LR organizer. Structures receptive to Nodal signaling expressing EGF-CFC receptors are shown in brown. (inset) Close-up of the LR organizer showing the relative positions of motile and nonmotile mechanosensory cilia, the direction of fluid flow, and the gradient of calcium. (B) Expression of nodal and cerberus around the LR organizer. This panel also shows gdf1/vg1 expression, and the diffusion of Nodal ligand and Cerberus antagonists to the lateral plate mesoderm. (C) Expansion of nodal, lefty, and pitx2 expression domains within the lateral plate mesoderm and notochord. The left panel shows the initial patch of nodal expression within the left lateral plate mesoderm, proximal to the LR organizer. (C′) Advance of nodal expression toward the anterior and posterior, followed by lefty2 and pitx2 expression within the lateral plate mesoderm, and lefty1 expression within the notochord. (C′′) Ultimate expression domain of nodal, lefty2, and pitx2 encompassing the entire left lateral plate mesoderm.

Figure 6.

Extracellular agonism and antagonism of bone morphogenetic protein (BMP) and Nodal during axis patterning. (A) References supporting and defining agonism and antagonism listed next to each connector. Expression domain of each species during axis patterning denoted by box color. (B–M) Conserved domains in each agonist and antagonist along with known binding domains. Note that additional binding partners that do not have a known binding domain determined by a structure–function analysis may exist. References to structure–function analysis shown for each binding domain. AA, amino acid; CR, cysteine-rich domain; Pro, Pro-domain; CC, coil–coil domain; DAN, differentially screening-selected gene arbitrative in neuroblastoma domain; Olfactomedin, olfactomedin domain; TM, transmembrane domain; Partial vWFD, Von Willebrand factor type D domain; Kaz, Kazal domain family Follistatin module; E, EGF domain; CUB, complement C1r/C1s-sea urchin epidermal growth factor-BMP-1; Protease, protease, Nog domain, Noggin domain; SFRP-1L, secreted frizzled-related protein domain; Chd, chordin; Chrd, chordin domain; TgfB-L, TGF-β-like domain; TIL, trypsin inhibitor-like cysteine-rich domain. Numbers 1 through 75 in panels A and B refer to the following references: 1, Agius et al. 2000; 2, Aykul and Martinez-Hackert 2016; 3, Aykul et al. 2015; 4, Ambrosio et al. 2008; 5, Bates et al. 2013; 6, Bayramov et al. 2011; 7, Bell 2003; 8, Belo et al. 2000; 9, Bijakowski et al. 2012; 10, Blader 1997; 11, Blitz et al. 2000; 12, Blitz et al. 2003; 13, Chang et al. 2001; 14, Chang et al. 2003; 15, Chen and Shen 2004; 16, Church et al. 2015; 17, Collavin 2003; 18, Connors et al. 1999; 19, Connors et al. 2006; 20, Dal-Pra et al. 2006; 21, Degenkolbe et al. 2013; 22, Feldman et al. 2002; 23, Geng et al. 2011; 24, Geach and Dale 2008; 25, Glister et al. 2004; 26, Glister et al. 2015; 27, Goodman et al. 1998; 28, Groppe et al. 1998; 29, Groppe et al. 2002; 30, Groppe et al. 2002; 31, Harms and Chang 2003; 32, Iemura et al. 1998; 33, Inomata et al. 2008; 34, Inomata et al. 2013; 35, Jasuja et al. 2006; 36, Katsu et al. 2012; 37, Khokha et al. 2005; 38, Kisonaite et al. 2016; 39,40, Larrain et al. 2000; 41, Larrain et al. 2001; 42, Lee et al. 2006; 43, Lee et al. 2009; 44, Marques et al. 2004; 45, Miller-Bertoglio et al. 1999; 46, Muraoka et al. 2006; 47, Oelgeschlager et al. 2000; 48, Oelgeschlager 2003; 49, Paine-Saunders et al. 2002; 50, Piccolo et al. 1997; 51, Piccolo et al. 1999; 52, Ploper et al. 2011; 53, Rentzsch et al. 2006; 54, Cha et al. 2006; 55, Salic et al. 1997; 56, Scott et al. 1999; 57, Scott et al. 2001; 58, Seemann et al. 2009; 59, Serpe et al. 2008; 60, Shibata et al. 2005; 61, Sidis et al. 2006; 62, Sun et al. 2006a; 63, Tanegashima et al. 2004; 64, Troilo et al. 2014; 65, Troilo et al. 2016; 66, Viviano et al. 2004; 67, Vonica and Brivanlou 2007; 68, Wardle et al. 1999; 69, Winstanley et al. 2015; 70, Xie and Fisher 2005; 71, Yabe 2003a; 72, Zhang et al. 2007; 73, Zhang et al. 2010; 74, Zimmerman et al. 1996; 75, Cheng et al. 2004.