G Model
ARTICLE IN PRESS
YSCDB-1586; No. of Pages 2
Seminars in Cell & Developmental Biology xxx (2014) xxx–xxx
Contents lists available at ScienceDirect
Seminars in Cell & Developmental Biology journal homepage: www.elsevier.com/locate/semcdb
Editorial
Ever developing TGF-
The discovery of TGF- dates back to 1978, with the detection by De Larco and Todaro of a secreted factor produced by virally transformed fibroblasts. This factor, released in the culture media, acted as a “non-cell autonomous oncogene” inducing normal fibroblast to grow in soft agar. It was a revealing demonstration that cell behavior could be profoundly affected by a new family of growth factors. TGF-1 was cloned few years later thanks to the joined efforts of the Sporn and Derynck laboratories. These pioneering discoveries were the dawn of what is now a very active area of investigation: the TGF- field now enlists a large family of cytokines, that includes Bone Morphogenetic Proteins (BMPs), endowed with a vast and ever expanding set of biological properties. Covering this amount of information is beyond the scopes of this journal, also considering the number of general and specialized reviews already available. Instead, we dedicated this special issue of Seminars in Cell and Developmental Biology to present some mature paradigms of TGF research, such the role of TGF- ligands in early development and left-right asymmetry, along with less explored and novel areas that have not been so extensively reviewed, such as the functions of TGF-/BMP growth factors in embryonic stem cells, organogenesis, tissue scaling and control of cell number. The Review from Robertson summarizes the multiple activities of Nodal, the critical TGF- ligand of the early embryo. Genetics studies over 20 years have firmly established the remarkable dynamicity of Nodal signaling: Nodal initially sustains pluripotency in the blastocyst; then, after implantation, provides positional information essential for the establishment of the body plan and, few hours later, Nodal orchestrates the first cell fate decisions of mammalian gastrulation. How the same Nodal signal acting through the same transduction cascade can trigger such a dynamic set of biological activities is still only partially understood. What is known is the fact that Nodal ligands are not evenly active in embryonic tissues, but finely patterned by a number of secreted antagonists, extracellular proteases and other cofactors. On the one hand, these factors provide context-specificity to the effects of Nodal, barring them in one group of cells and enabling them in another; on the other hand, the same factors establish gradients of Nodal signaling causing identical cells to adopt different fates according to signal intensity or duration they experience. The functions of Nodal continue after gastrulation in the definition of the left-right axis. This is the topic of the Shiratori and Hamada review. They summarize how the antagonism between Nodal and its extracellular inhibitors, such as Cerl2 and Lefty, progressively confines Nodal activity and expression to the left side of
the developing embryo. Intriguingly, the initial symmetry-breaking event is a mechanical cue: the leftward flow of extracellular fluid caused by the movement of cilia present in the node cells, that is, in the tissue that orchestrates mouse gastrulation. Through unknown mechanisms, the leftward fluid flow causes Cerl2 mRNA degradation on the left side unbalancing Nodal signaling and initiating a cascade of molecular and cellular events that brings about the asymmetric arrangements of the visceral organs. Even before the cloning of TGF-, it was already known that the molecule was secreted in a biologically inactive form and that its activity could be unleashed by acidification or other harsh treatments. The biochemical nature of this “TGF- latency” remained enigmatic until it was recognized that proteases of the proprotein convertase family clip the TGF- precursor, but this remains attached to and masked within its pro-domain. The physiological mechanisms that normally unmask TGF- ligands are only partially understood. The review by Constam summarizes classic and more recent data on TGF- proteolytic processing and its own regulation in shaping gradients of TGF- ligands during development and to localize TGF- activity in cancer. An important aspect in TGF- research focuses on the role of this signaling cascade in the regulation of pluripotency in embryonic stem (ES) cells. As highlighted in the reviews of Itoh et al., and of Gaarenstroom and Hill there are important differences between human and mouse ES cells. In mouse ES cells, BMP signaling maintains pluripotency, while TGF- promotes differentiation; in contrast, TGF- is required for pluripotency of human ES cells, while BMPs prompt their differentiation. Nodal signaling can directly interlace with the ES cells pluripotency network (i.e., expression of Oct4, Sox2, Nanog); that said, a dominant function of TGF-/BMP ligands and their intracellular transducers, the Smads transcription factors, is the regulation of genes involved in ES cells differentiation along the neural, mesodermal and endodermal lineages. As outlined by Itoh et al., positive and negative regulations of TGF- ligands can redirect pluripotent cells toward progressively more committed fates; indeed TGF-/BMP agonists or antagonists are elements of the cocktails of extrinsic factors currently employed in the manipulation of ES and iPS cells for future regenerative medicine applications. Gaarenstroom and Hill then cover in more detail how the context-specific and dose-dependent effects of Smads are realized: the arrival of ligand-activated Smads in the nucleus represents an important signal but, per se, largely void of specific instructions. It is the cromatin context, and thus the cell’s own genetic and epigenetic
http://dx.doi.org/10.1016/j.semcdb.2014.04.033 1084-9521/© 2014 Published by Elsevier Ltd.
Please cite this article in press as: http://dx.doi.org/10.1016/j.semcdb.2014.04.033
Piccolo
S.
Ever
developing
TGF-.
Semin
Cell
Dev
Biol
(2014),
G Model YSCDB-1586; No. of Pages 2 2
ARTICLE IN PRESS Editorial / Seminars in Cell & Developmental Biology xxx (2014) xxx–xxx
history, that canalizes Smad in the selection of specific, somehow pre-set, transcriptional programs. Clearly, TGF- and BMP ligands do not act in isolation but crosstalk with a host of other signals that the cells receive from the microenvironment. Pignatti et al. review a remarkable example of morpho-regulatory interactions between BMPs, their antagonist Gremlin, and other growth factor pathways in several steps of limb bud development, from specification, to definition of signaling centers and finally specification of limb skeletal primordia. A strength of the TGF- field is represented by its deep roots into Drosophila genetics. The importance of TGF- ligands in that model system became immediately important in the very early days of TGF- research, when Gelbart and collaborators identified in 1982 the decapentaplegic gene (dpp), a mutant with dramatic phenotypes associated to aberrant dorso-ventral patterning. The capacity of dpp to serve as long-range morphogen in embryonic tissues was then further demonstrated in the fly wing imaginal disk. Despite years of research, many aspects of dpp biology, logic and mechanisms remain poorly understood. And this is not surprising, given that fly dpp, just like mouse Nodal, remains a paradigm for TGF- research, continuing to offer universal insights into related processes of vertebrates. This is the topic of the Hamaratoglu et al., review. Among of the newer aspects that they cover are the roles of Dpp in stem cells and the function of dpp in organ growth control, regeneration and the proportional scaling of organ and body size.
Please cite this article in press as: http://dx.doi.org/10.1016/j.semcdb.2014.04.033
Piccolo
S.
In connection to these issues, the last review of this issue from Baillon and Basler focuses on the phenomenon of cell competition. Originally uncovered in Drosophila, cell competition is a universal by which a tissue self-controls its own composition and cellular homogeneity, for example eliminating dying or mutant cells in a non-cell autonomous manner. Cell competition, which is regulated by dpp and Hippo signaling, is critical for cancer research: elimination of mutant, aberrant epithelial cells is likely a potent barrier to tumor development in adult tissues; however, as the tumor progresses, cell competition becomes a foe, driving cancer cells expansion at the border with the normal tissues. Once again, understanding of such mysterious, yet obviously very relevant biological process will continue to greatly benefit from the genetic toolbox developed in Drosophila. In sum, we hope this issue of Seminars in Cell and Developmental Biology will be useful to the experts and intrigue the newcomers attracted to the many wonders of TGF- biology. Stefano Piccolo 1 Department of Molecular Medicine, University of Padua School of Medicine, viale Colombo 3, 35126 Padova, Italy E-mail address: [email protected] 1
http://www.bio.unipd.it/piccolo/. Available online xxx
Ever
developing
TGF-.
Semin
Cell
Dev
Biol
(2014),
ARTICLE IN PRESS
YSCDB-1586; No. of Pages 2
Seminars in Cell & Developmental Biology xxx (2014) xxx–xxx
Contents lists available at ScienceDirect
Seminars in Cell & Developmental Biology journal homepage: www.elsevier.com/locate/semcdb
Editorial
Ever developing TGF-
The discovery of TGF- dates back to 1978, with the detection by De Larco and Todaro of a secreted factor produced by virally transformed fibroblasts. This factor, released in the culture media, acted as a “non-cell autonomous oncogene” inducing normal fibroblast to grow in soft agar. It was a revealing demonstration that cell behavior could be profoundly affected by a new family of growth factors. TGF-1 was cloned few years later thanks to the joined efforts of the Sporn and Derynck laboratories. These pioneering discoveries were the dawn of what is now a very active area of investigation: the TGF- field now enlists a large family of cytokines, that includes Bone Morphogenetic Proteins (BMPs), endowed with a vast and ever expanding set of biological properties. Covering this amount of information is beyond the scopes of this journal, also considering the number of general and specialized reviews already available. Instead, we dedicated this special issue of Seminars in Cell and Developmental Biology to present some mature paradigms of TGF research, such the role of TGF- ligands in early development and left-right asymmetry, along with less explored and novel areas that have not been so extensively reviewed, such as the functions of TGF-/BMP growth factors in embryonic stem cells, organogenesis, tissue scaling and control of cell number. The Review from Robertson summarizes the multiple activities of Nodal, the critical TGF- ligand of the early embryo. Genetics studies over 20 years have firmly established the remarkable dynamicity of Nodal signaling: Nodal initially sustains pluripotency in the blastocyst; then, after implantation, provides positional information essential for the establishment of the body plan and, few hours later, Nodal orchestrates the first cell fate decisions of mammalian gastrulation. How the same Nodal signal acting through the same transduction cascade can trigger such a dynamic set of biological activities is still only partially understood. What is known is the fact that Nodal ligands are not evenly active in embryonic tissues, but finely patterned by a number of secreted antagonists, extracellular proteases and other cofactors. On the one hand, these factors provide context-specificity to the effects of Nodal, barring them in one group of cells and enabling them in another; on the other hand, the same factors establish gradients of Nodal signaling causing identical cells to adopt different fates according to signal intensity or duration they experience. The functions of Nodal continue after gastrulation in the definition of the left-right axis. This is the topic of the Shiratori and Hamada review. They summarize how the antagonism between Nodal and its extracellular inhibitors, such as Cerl2 and Lefty, progressively confines Nodal activity and expression to the left side of
the developing embryo. Intriguingly, the initial symmetry-breaking event is a mechanical cue: the leftward flow of extracellular fluid caused by the movement of cilia present in the node cells, that is, in the tissue that orchestrates mouse gastrulation. Through unknown mechanisms, the leftward fluid flow causes Cerl2 mRNA degradation on the left side unbalancing Nodal signaling and initiating a cascade of molecular and cellular events that brings about the asymmetric arrangements of the visceral organs. Even before the cloning of TGF-, it was already known that the molecule was secreted in a biologically inactive form and that its activity could be unleashed by acidification or other harsh treatments. The biochemical nature of this “TGF- latency” remained enigmatic until it was recognized that proteases of the proprotein convertase family clip the TGF- precursor, but this remains attached to and masked within its pro-domain. The physiological mechanisms that normally unmask TGF- ligands are only partially understood. The review by Constam summarizes classic and more recent data on TGF- proteolytic processing and its own regulation in shaping gradients of TGF- ligands during development and to localize TGF- activity in cancer. An important aspect in TGF- research focuses on the role of this signaling cascade in the regulation of pluripotency in embryonic stem (ES) cells. As highlighted in the reviews of Itoh et al., and of Gaarenstroom and Hill there are important differences between human and mouse ES cells. In mouse ES cells, BMP signaling maintains pluripotency, while TGF- promotes differentiation; in contrast, TGF- is required for pluripotency of human ES cells, while BMPs prompt their differentiation. Nodal signaling can directly interlace with the ES cells pluripotency network (i.e., expression of Oct4, Sox2, Nanog); that said, a dominant function of TGF-/BMP ligands and their intracellular transducers, the Smads transcription factors, is the regulation of genes involved in ES cells differentiation along the neural, mesodermal and endodermal lineages. As outlined by Itoh et al., positive and negative regulations of TGF- ligands can redirect pluripotent cells toward progressively more committed fates; indeed TGF-/BMP agonists or antagonists are elements of the cocktails of extrinsic factors currently employed in the manipulation of ES and iPS cells for future regenerative medicine applications. Gaarenstroom and Hill then cover in more detail how the context-specific and dose-dependent effects of Smads are realized: the arrival of ligand-activated Smads in the nucleus represents an important signal but, per se, largely void of specific instructions. It is the cromatin context, and thus the cell’s own genetic and epigenetic
http://dx.doi.org/10.1016/j.semcdb.2014.04.033 1084-9521/© 2014 Published by Elsevier Ltd.
Please cite this article in press as: http://dx.doi.org/10.1016/j.semcdb.2014.04.033
Piccolo
S.
Ever
developing
TGF-.
Semin
Cell
Dev
Biol
(2014),
G Model YSCDB-1586; No. of Pages 2 2
ARTICLE IN PRESS Editorial / Seminars in Cell & Developmental Biology xxx (2014) xxx–xxx
history, that canalizes Smad in the selection of specific, somehow pre-set, transcriptional programs. Clearly, TGF- and BMP ligands do not act in isolation but crosstalk with a host of other signals that the cells receive from the microenvironment. Pignatti et al. review a remarkable example of morpho-regulatory interactions between BMPs, their antagonist Gremlin, and other growth factor pathways in several steps of limb bud development, from specification, to definition of signaling centers and finally specification of limb skeletal primordia. A strength of the TGF- field is represented by its deep roots into Drosophila genetics. The importance of TGF- ligands in that model system became immediately important in the very early days of TGF- research, when Gelbart and collaborators identified in 1982 the decapentaplegic gene (dpp), a mutant with dramatic phenotypes associated to aberrant dorso-ventral patterning. The capacity of dpp to serve as long-range morphogen in embryonic tissues was then further demonstrated in the fly wing imaginal disk. Despite years of research, many aspects of dpp biology, logic and mechanisms remain poorly understood. And this is not surprising, given that fly dpp, just like mouse Nodal, remains a paradigm for TGF- research, continuing to offer universal insights into related processes of vertebrates. This is the topic of the Hamaratoglu et al., review. Among of the newer aspects that they cover are the roles of Dpp in stem cells and the function of dpp in organ growth control, regeneration and the proportional scaling of organ and body size.
Please cite this article in press as: http://dx.doi.org/10.1016/j.semcdb.2014.04.033
Piccolo
S.
In connection to these issues, the last review of this issue from Baillon and Basler focuses on the phenomenon of cell competition. Originally uncovered in Drosophila, cell competition is a universal by which a tissue self-controls its own composition and cellular homogeneity, for example eliminating dying or mutant cells in a non-cell autonomous manner. Cell competition, which is regulated by dpp and Hippo signaling, is critical for cancer research: elimination of mutant, aberrant epithelial cells is likely a potent barrier to tumor development in adult tissues; however, as the tumor progresses, cell competition becomes a foe, driving cancer cells expansion at the border with the normal tissues. Once again, understanding of such mysterious, yet obviously very relevant biological process will continue to greatly benefit from the genetic toolbox developed in Drosophila. In sum, we hope this issue of Seminars in Cell and Developmental Biology will be useful to the experts and intrigue the newcomers attracted to the many wonders of TGF- biology. Stefano Piccolo 1 Department of Molecular Medicine, University of Padua School of Medicine, viale Colombo 3, 35126 Padova, Italy E-mail address: [email protected] 1
http://www.bio.unipd.it/piccolo/. Available online xxx
Ever
developing
TGF-.
Semin
Cell
Dev
Biol
(2014),
