You will be presented with the abstract, introduction, and discussion section from a biomedical research article. Your task is to create a summary that a layperson can understand, capturing the essence of the research article. Keep essential scientific terms, but ensure that the language remains clear and the concepts are explained in an uncomplicated manner.

Title: Bone morphogenic protein signalling suppresses differentiation of pluripotent cells by maintaining expression of E-Cadherin}
Article:
Abstract:
Bone morphogenic protein( BMP) signalling contributes towards maintenance of pluripotency and favours mesodermal over neural fates upon differentiation, but the mechanisms by which BMP controls differentiation are not well understood. We report that BMP regulates differentiation by blocking downregulation of Cdh1, an event that accompanies the earliest stages of neural and mesodermal differentiation. We find that loss of Cdh1 is a limiting requirement for differentiation of pluripotent cells, and that experimental suppression of Cdh1 activity rescues the BMP-imposed block to differentiation. We further show that BMP acts prior to and independently of Cdh1 to prime pluripotent cells for mesoderm differentiation, thus helping to reinforce the block to neural differentiation. We conclude that differentiation depends not only on exposure to appropriate extrinsic cues but also on morphogenetic events that control receptivity to those differentiation cues, and we explain how a key pluripotency signal, BMP, feeds into this control mechanism.
Introduction:
The events that drive the transition from pluripotency to lineage commitment remain poorly understood. It has been known for many years that BMP signalling protects pluripotency and suppresses neural specification( Ying et al., 2003a; Stern, 2006; Di-Gregorio et al., 2007), but the underlying mechanisms remain unclear. BMP signalling is also required for the formation of mesoderm in vivo( Mishina et al., 1995; Winnier et al., 1995; Lawson et al., 1999; Beppu et al., 2000; Davis et al., 2004), and BMP is commonly used to induce mesoderm from embryonic stem( ES) cells( Murry and Keller, 2008). However, it is not clear how the effects of BMP on mesoderm differentiation relate to its pro-pluripotency and anti-neural effects: are these separable independent events or do they represent the outcomes of one common mechanism? This question underlines our poor understanding of the mechanisms by which BMP influences neural and mesodermal specification. BMP acts through transcriptional upregulation of Inhibitor of Differentiation( Id) factors( Ying et al., 2003a; Zhang et al., 2010) in order to prevent neural differentiation. Id factors generally act as dominant negative inhibitors of the bHLH family of transcription factors( Norton, 2000), but the mechanism by which Id proteins block neural induction is not known. Furthermore, it is not clear to what extent the pro-mesoderm effect of BMP within the epiblast is mediated by Id or by other BMP target genes: redundancy between the four Id family members may mask gastrulation phenotypes in Id mutants. We set out to examine more closely the effects of BMP and Id1 on neural and mesoderm differentiation by taking advantage of an ES cell differentiation system, which allows differentiation to be carefully monitored in a well-defined environment( Ying and Smith, 2003), and by using a reporter strategy to ask which cells usually express Id1 during early development. We find an unanticipated ability of BMP/Id to block differentiation by maintaining the expression of the cell adhesion molecule E-Cadherin( Cdh1). We find that loss of Cdh1 is tightly associated with neural as well as mesodermal differentiation and that this change in Cdh1 is a limiting requirement for neural differentiation. A number of recent reports( Chou et al., 2008; Soncin et al., 2009; Li et al., 2010; Redmer et al., 2011; del Valle et al., 2013; Faunes et al., 2013) suggest that Cdh1 helps protect pluripotency. Despite this emerging appreciation of Cdh1 as a regulator of the pluripotent state, the upstream regulators of Cdh1 in pluripotent cells have not been reported. BMP favours mesenchymal to epithelial transitions in other contexts( Kondo et al., 2004; Samavarchi-Tehrani et al., 2010), but its ability to control Cdh1 activity during early fate specification has not previously been appreciated. We also find that BMP acts through Id1 to impose a proximal posterior identity on epiblast cells, priming them for mesodermal fates whilst transiently restraining them from overt mesoderm differentiation. Id1 may therefore play an early role in anterior-posterior( AP) patterning and mesoderm priming, independent from any effect on overt mesoderm differentiation. This helps to reconcile why BMP is required both for mesoderm differentiation and for the maintenance of pluripotency. Taken together, our data help to unify the distinct effects of BMP signalling during differentiation of pluripotent cells. BMP maintains high levels of Cdh1, which help to protect the pluripotent state, whilst imposing a posterior identity that ultimately favours mesodermal over neural differentiation.
Discussion:
Changes in the expression of the cell-cell adhesion molecule E-Cadherin( Cdh1) are often associated with changes in cell identity throughout development and into adult life( Thiery et al., 2009). For example, downregulation of Cdh1 is associated with the epithelial-mesenchymal transition( EMT) that accompanies the formation of mesoderm at the primitive streak and the emergence of neural crest cells from the dorsal neural tube( Thiery et al., 2009). The formation of the early neural plate from the epiblast does not bear all the hallmarks of a classical EMT, but it is accompanied by loss of Cdh1 and gain of N-Cadherin( Cdh2) and Vimentin( Hatta and Takeichi, 1986; Aaku-Saraste et al., 1996). There is already evidence that EMT is required for overt mesoderm differentiation( Martínez-Estrada et al., 2010), and we find here that downregulation of Cdh1 is similarly a limiting event for neural differentiation. Although it is well established that BMP signalling contributes to the maintenance of pluripotency( Ying et al., 2003a; Di-Gregorio et al., 2007), the underlying mechanisms remain unclear. We propose that BMP suppresses differentiation by maintaining expression of Cdh1. We support this idea by showing that suppressing Cdh1 is sufficient to rescue the BMP-imposed block to multilineage differentiation. It is also unclear how BMP signalling favours mesodermal over neural fates. We find that the BMP target gene Id1 imposes a proximal posterior identity on undifferentiated cells, priming them towards mesoderm. The ability of Id1 to block neural differentiation is therefore unlikely to be explained entirely by inhibition of a neural-inducing transcription factor as is commonly assumed, nor by a direct activation of mesoderm differentiation, but rather to a shift in the positional identity of pluripotent cells that occurs in the absence of overt differentiation. This may explain why, to our knowledge, no Id-regulated pro-neural bHLH transcription factor has been found that explains the ability of Id1 to influence neural induction. Id1 null ES cells have a defect in the maintenance of pluripotency( Romero-Lanman et al., 2011), consistent with our finding that Id1 delays exit from an epiblast-like state. We note, though, that the Id1 null phenotype is also likely to reflect an earlier pre-implantation role for Id1: to suppress the activity of Tcf15( Davies et al., 2013). The consequence of this would be to maintain expression of Nanog and suppress the transition to a T+ epiblast-like state( Davies et al., 2013), in keeping with the Id1 null ES cell phenotype( Romero-Lanman et al., 2011). The two effects of BMP, to maintain Cdh1 and to impose a posterior identity, can be uncoupled by varying the dose of BMP. Lower doses of BMP are sufficient to maintain Cdh1 and to suppress neural fate, but insufficient to impose a stable posterior identity. Strikingly, suppressing Cdh1 at these lower doses of BMP is sufficient to rescue neural differentiation, indicating that the primary mechanism by which BMP inhibits neural differentiation in this context is through its ability to control Cadherin activity. This is an unexpected finding that highlights the importance of cell adhesion and tissue organisation in controlling receptivity of cells to differentiation cues( Stepniak et al., 2009; Faunes et al., 2013). There is a growing body of evidence that Cdh1 influences growth factor receptiveness of ES cells, and that it can consequently stabilise particular pluripotent states( Chou et al., 2008; Soncin et al., 2009; Li et al., 2010; Redmer et al., 2011; Hawkins et al., 2012; del Valle et al., 2013; Faunes et al., 2013), but it is not known what controls Cdh1 expression in this context. We fill this gap with our finding that BMP/Id maintains Cdh1 expression during differentiation of ES cells. Interestingly, Id1 is excluded from the anterior streak in vivo( Jen et al., 1997), so it is possible that it plays a more general role in regulating EMT in the early embryo. In vivo, the BMP signals that are generated from the extraembryonic ectoderm not only block neural induction but are also required for formation of mesoderm( Mishina et al., 1995; Winnier et al., 1995; Lawson et al., 1999; Beppu et al., 2000; Davis et al., 2004). However, BMP signalling is also necessary for maintenance of pluripotency( Di-Gregorio et al., 2007), and mouse embryos in which BMP has been experimentally overactivated have an impairment in mesoderm differentiation that cannot easily be explained by models in which BMP drives mesoderm differentiation( Aoyama et al., 2012). Our findings unite these observations by showing how BMP can prime cells for mesoderm fate by imposing a posterior identity, but restrain them from undergoing overt mesoderm formation by suppressing EMT. In frogs, antagonism of BMP by the organiser induces anterior-posterior axis formation. It has been proposed( Constance Lane et al., 2004) that BMP antagonism acts by stimulating mediolateral intercalation of caudal progenitors, releasing them to participate in the formation of the axis, and that the normal role of BMP is to preserve a reservoir of progenitors throughout axis elongation. We propose that BMP acts by a similar mechanism during differentiation of pluripotent mouse cells, preserving a population of undifferentiated cells by preventing the loss of Cdh1. The mechanism by which BMP signalling controls EMT will be an interesting area for future study. This may be connected with BMP’s ability to antagonise Nodal signalling, given that Nodal is required for the initiation of EMT at the primitive streak( Arnold and Robertson, 2009; Yan et al., 2009). Our work also has implications for controlling uniform differentiation of mouse ES cells. It has been known for some time that a subpopulation of ES cells tends to resist neural differentiation, but the reasons for this are not clear. We propose that this subpopulation of cells fail to respond appropriately to a neural-inducing environment because they are unable to downregulate Cdh1. We demonstrate this directly by showing that experimental suppression of Cdh1 activity can rescue neural differentiation capacity in this recalcitrant subpopulation resulting in a more homogenous differentiation response. Importantly, this can be achieved by non-genetic means, such as function-blocking E-Cadherin antibodies, providing a convenient and readily applicable means to improve our control over pluripotent cells. In summary, we have identified the loss of Cdh1 activity as a limiting event for the earliest stages of neural differentiation and we propose that BMP controls differentiation in part by maintaining Cdh1 expression. The strategy of coupling changes in cell adhesion to transcriptional control of cell fate specification is used several times during development as a way of coordinating tissue morphogenesis( Owens et al., 2000; Martínez-Estrada et al., 2010; Watt and Fujiwara, 2011), and it will be interesting to investigate the implications of our findings for germ-layer formation in the early embryo.
The human body is made up of about 200 different types of cell , all of which are descended from a single fertilised egg . As an embryo develops , its cells divide and specialise into distinct lineages . Cells in each lineage go on to form a restricted number of cell types that are required to make a specific tissue . As such , during early development , cells switch from being ‘pluripotent’ , with the potential to become the many different cell types , to committing to one particular cell lineage . Controlling this process involves a huge number of signalling proteins and pathways . One such protein is bone morphogenetic protein , or BMP for short , which has a number of different roles in embryo development: for example , it stops pluripotent cells turning into nerve tissue , and it also encourages embryonic stem cells to contribute to the ‘mesoderm’ of the early embryo ( which goes on to form the muscles , connective tissues and some blood cells ) . How these two actions are linked , and whether they depend on similar signalling pathways , was unknown . BMP is also known to trigger the production of proteins known as ‘Id factors’—which stands for ‘inhibitor of differentiation’ . Now , Malaguti et al . have investigated the roles of BMP and Id factors in controlling mouse embryo development and found , somewhat surprisingly , that these proteins needed help from a third protein to stop pluripotent cells turning into nerve tissue . This third protein , which is called E-Cadherin , normally helps cells to adhere to other cells . Malaguti et al . showed that losing this protein encourages cells to become either nerve or mesoderm tissues , and that a drop in E-Cadherin levels must occur before nerve tissue can form . Malaguti et al . also showed that encouraging cells to become part of the mesoderm requires BMP to activate another pathway , which does not require E-Cadherin . The two effects of BMP can be uncoupled by adjusting the levels of this protein . At low concentrations , BMP can keep cells pluripotent , but it cannot encourage cells to commit to a mesoderm fate . At higher doses , however , BMP ‘primes’ cells to respond to the signals that trigger their development into mesoderm tissue . The findings of Malaguti et al . suggest that manipulating both E-Cadherin and BMP signalling could improve our ability to generate useful cell types , such as neurons , from stem cells grown in laboratory cultures .