Chapter 7 Communication between cells is a fundamental requirement for their growth and differentiation and also for embryological development. To facilitate effective cellular communication, diverse signalling mechanisms have evolved which enable complex multicellular organisms to develop and to function in an effective and coordinated manner. Events associated with the initiation of cellular differentiation, leading to the formation of tissues and organs and ultimately to the development of a new member of a species, are mediated by a relatively small number of highly conserved signalling pathways. Although the basis for the genetic development of an individual is already encoded in the zygote, establishment of this plan requires that effective communication between cells be coordinated and accurate, both in timing and intensity. As disturbances of these communication processes are likely to adversely affect normal embryological development, signalling mechanisms which operate during development must be precise, reliable and reproducible. Within tissues and organs, there are many different mechanisms whereby signals can be relayed to recipient cells. Short‐range signalling mechanisms, such as cell‐to‐cell, paracrine and autocrine signalling, have a fundamental role in early embryological development. As the complexity of a developing embryo increases, long‐range signalling mechanisms become a requirement. The consequences of cell signalling can be diverse and, depending on the nature and cellular interpretation of the signal, recipient cells may be induced to alter their function, divide, differentiate, change their morphology, migrate, adhere to each other or, in some instances, undergo apoptosis (Fig 7.1). Figure 7.1 Cellular responses induced by extracellular signals. A. Cell division. B. Differentiation. C. Morphological change. D. Apoptosis. Delivery of signalling molecules can be achieved by short‐range mechanisms such as paracrine, autocrine and contact‐dependent signalling along with long‐range communication, including synaptic and endocrine signalling (Fig 7.2). Figure 7.2 Short‐range and long‐range signalling mechanisms. Short‐range mechanisms include A, paracrine signalling, B, contact‐dependent signalling, and C, autocrine signalling. Long‐range mechanisms include D, synaptic signalling and E, endocrine signalling. The term paracrine signalling describes a form of short‐range signalling which does not require direct cell‐to‐cell contact (Fig 7.2A). In this instance, messenger molecules secreted by a cell usually reach nearby cells by diffusion through the extracellular matrix (ECM), where they are bound by target cells in close proximity. Paracrine signalling molecules can, however, be restricted by the properties of the ECM, thereby ensuring that their effects are directed exclusively to target cells. A form of short‐range communication, referred to as contact‐dependent signalling, requires that the cell emitting the signal be in direct contact with its target cells (Fig 7.2B). This form of signalling is of particular importance during early development. There are three types of contact‐dependent signalling. In the first type, a signalling molecule, typically a protein in the cell membrane, binds to specific receptors on the membranes of adjacent cells. The second type of cell‐to‐cell signalling involves secretion of a ligand into the immediate cellular environment which then binds to a receptor on the target cell. In the third type, a signal is transmitted directly from the cytoplasm of one cell to the cytoplasm of adjacent cells through gap junctions. Cells can transmit signals to cells of a similar type or sometimes to themselves (Fig 7.2C). This type of signalling, termed autocrine signalling, has an important role during early embryonic development when groups of cells of the same type can influence clusters of similar cells to follow a common developmental pathway. Long‐range signalling, such as that which occurs with neurons, is referred to as synaptic signalling (Fig 7.2D). By this means, signals are transmitted rapidly and specifically to distant regions of the developing organism. In common with synaptic signalling, endocrine signalling can act on distant targets (Fig 7.2E). The molecules involved in endocrine signalling can be delivered to target tissues by diffusion or haematogenously. In comparison with synaptic signalling, this type of signalling tends to be relatively slow in inducing a response. The effects of endocrine signals are often long‐lived and a relatively small number of signalling molecules can induce widespread and sustained activation of target cells. Eleven main classes of signalling pathways participate in embryological development. These include Notch, fibroblast growth factor (Fgf), epidermal growth factor (Egf), Wingless (Wnt), Hedgehog (Hh), transforming growth factor β (Tgf‐β), Janus Kinase signal transducers and activators of transcription (JAK‐STAT) pathway, Hippo, Jun kinase (JNK), NF‐kβ and retinoic acid receptor (RAR). Among the pathways listed, only two, Notch and Hippo, are contact dependent while the remaining pathways are paracrine in nature. These signalling pathways regulate many processes and can elicit diverse effects. Depending on the state of cellular differentiation, processes activated by these pathways include determination of cell fate, apoptosis, proliferation, cytoskeletal reorganisation, polarity, adhesion and cell migration. Although particular signalling pathways have distinct molecular components and regulatory mechanisms, a number of common features have emerged relating to their regulation in time and space. During embryological development, signals appear to be transmitted in a linear manner within a cell. This is in contrast to signalling pathways in adult animals which have multiple converging and diverging links. The changes generated by signals during development are usually irreversible and therefore require certainty in their delivery and interpretation. This principle holds true for both ‘on/off’ and gradient‐type signalling. Each pathway regulates the activity of one or more transcription factors, which in turn bind to specific signalling response elements located in the enhancers and promoters of target genes. Signalling must be precise for the reproduction of patterns of development in a given species. Negative feedback mechanisms provide additional fine‐tuning over a range of signalling levels, further defining the boundaries between regions while also buffering against extraneous signals. Noggin is an example of a negative regulator which inhibits Tgf‐β signalling by binding to Tgf‐β ligands, thereby preventing these ligands from binding to their receptors. Several mechanisms have been identified for generating transcriptional thresholds at which transcriptional activation of target genes occurs. In the case of contact‐dependent signalling, the ligand is membrane bound and hence the boundaries of signalling are dictated by the contact zones between the transmitting and receiving cells. Where the ligand is diffusible, a graded signalling profile is generated which converts to sharp borders of induction, based on its levels of expression. During organ morphogenesis, a particular group of cells can influence the fate of an adjacent group of cells. This close range interaction is termed induction, a process which is generally mediated by paracrine and contact‐dependent signalling. The signals which a cell receives during induction depend on the cell’s microenvironment in addition to its competence to receive, interpret and respond to these signals. Two forms of induction are recognised: instructive and permissive. Instructive induction is the process whereby a cell follows a particular developmental pathway in response to given signals but a different pathway in the absence of these signals. Permissive induction describes the circumstances in which the responding cell is already committed to a particular developmental fate but requires additional inducing signals to continue along that pathway. Progressive complexity arises in the developing organism through a series of inductive steps termed sequential induction. Through sequential induction, the basic body plan of the early embryo becomes established. Subsequently, refinement of this plan results in enhanced functional and morphological complexity. The term competence refers to a cell’s ability to respond to certain inductive signals. A competent cell must have a receptor capable of binding the signalling molecules. In addition to this feature, it must have an intracellular signal transducing apparatus capable of forming a link with the final intracellular target. An example of this form of interaction is the activation of individual genes or sets of genes by transcription factors. A cell which is undergoing induction by neighbouring cells through cell‐to‐cell signalling mechanisms may lose its competence by breaking contact with the inducing cell as a consequence of cellular migration. In vertebrates, the chemical messages transmitted by cells are diverse. These signals may take the form of proteins, small peptides, amino acids, nucleotides, steroids, fatty acids, dissolved gases, simple molecules or ions. Broadly speaking, these signalling factors can be divided into extracellular and intracellular signalling molecules. The molecules which mediate signalling are typically released by exocytosis or diffusion from the cells in which they originate. The receptors present on the surface of the receiving cell are structurally diverse and include G‐protein receptors, ion channel receptors, tyrosine kinase receptors, serine–threonine receptors and members of the steroid receptor superfamily. G‐protein receptors function by activating intracellular G‐proteins which, in turn, bind guanosine triphosphate (GTP) and influence biochemical activities by conversion of GTP to guanosine diphosphate (GDP) with the release of energy. As a family, G‐protein receptors are the most diverse of all the membrane‐bound receptors in terms of both structure and function. They are involved in the recognition and transduction of signals from proteins, calcium ions and other small molecules. Ion channel receptors influence intracellular activities by regulating the movement of small molecules such as potassium and sodium ions across cell membranes. Tyrosine kinase receptors, such as fibroblast growth factor receptors, activate intracellular proteins via tyrosine phosphorylation. Serine–threonine receptors activate intracellular proteins by serine or threonine phosphorylation. Members of the transforming growth factor‐β superfamily act through serine–threonine‐type receptors. Members of the steroid receptor superfamily, which can be present in the cytosol or on the nuclear membrane, interact with hydrophobic signalling molecules capable of diffusing across the plasma membrane. These receptors contain ligand‐binding, DNA‐binding and transcription‐activation domains. Oestrogen and thyroid hormone receptors belong to the steroid receptor superfamily. Numerous fundamental developmental events are mediated by paracrine factors, including the Hedgehog family, the fibroblast growth factor family, the Wingless family and the transforming growth factor‐β superfamily and by contact‐dependent signalling, including Notch. Members of the Hedgehog family of intercellular signalling molecules are recognised as key mediators of many fundamental processes during development. Three mammalian homologues of the Hedgehog gene, first identified in Drosophila, have been characterised. These homologues are Sonic Hedgehog (Shh), Indian Hedgehog (Ihh) and Desert Hedgehog (Dhh). The effect of Hedgehog signals on cell fate specification, proliferation and survival is influenced by the microenvironment. The Shh gene encodes a signalling protein which is central to the establishment of the body plan during early embryogenesis. Shh is expressed in the primitive node and throughout the notochord, in the floorplate of the neural tube, in early gut endoderm and in the limb buds. The initial stage in Hedgehog signal transduction involves the binding of the Hedgehog ligand Patched (Ptc). In the absence of ligand, Ptc inhibits the G‐coupled receptor Smo (Figs 7.3A and B) This repression results in the accumulation of the transcription factors Cubitus interruptus (Ci) (in Drosophila) and Gli (in vertebrates) which, following proteolytic cleavage, become transcriptional repressors CiR and GLi3R respectively. In vertebrates, there are three Gli transcription factors encoded, each with distinct functions which operate in a combinatorial fashion to direct cell fate. Alternatively, when Hedgehog binds Ptc, it interacts with Smoothened (Smo) such that it is no longer inhibited, enabling the Ci/Gli protein to enter the nucleus where it promotes the expression of target genes (Fig 7.3). Cyclopia is associated with interruptions to Shh signalling. The developmental consequences associated with defects in Shh, its homologues and intracellular mediators are outlined in Table 7.1. Figure 7.3 The Hedgehog signalling transduction pathway illustrating the mechanisms of intracellular signalling in response to activation by the Hedgehog protein in A, Drosophila and B, mammals. Table 7.1 The mediators of Shh signalling for Drosophila and mammals, their activity in mammalian species and the developmental consequences associated with defects in these signalling molecules or receptors.
Cell signalling and gene functioning during development
Types of signalling
Paracrine signalling
Contact‐dependent signalling
Autocrine signalling
Synaptic signalling
Endocrine signalling
Signalling pathways
Signal regulation during development
Induction and competence
Cellular messengers and receptors
Paracrine and contact‐dependent signalling during embryological development
Hedgehog family
Drosophila
Mammals
Activity in mammalian species
Developmental or other consequences in mammals associated with defects in these signalling molecules or receptors
Signalling molecule
Hedgehog (Hh)
Sonic Hedgehog (Shh)
The protein encoded by Sonic Hedgehog is instrumental in patterning the early embryo. It has been identified as the key inductive signal in patterning of the ventral neural tube, the anterior‐posterior limb axis and the ventral somites.
Holoprosencephaly
Cyclopia
Semilobar holoprosencephaly
Polydactyly
Cleft lip
Desert Hedgehog (Dhh)
During development in the mouse, Dhh mRNA shows a very restricted distribution, with expression primarily in Sertoli cells of developing testes and in Schwann cells of peripheral nerves.
Gonadal dysgenesis
Indian Hedgehog (Ihh)
The encoded protein specifically plays a role in bone growth and differentiation.
Brachydactyly
Acrocapitofemoral dysplasia
Acrocallosal syndrome
Receptor
Patched (Ptc)
Patched (Ptch)
This gene encodes a member of the patched gene family which is the receptor for Shh, Dhh and Ihh proteins and functions as a tumour suppressor.
Basal cell nevus syndrome
Oesophageal squamous cell carcinoma Trichoepitheliomas,
Holoprosencephaly
Smoothened (Smo)
Smoothened (Smo)
G protein‐coupled receptor that associates with the patched protein (Ptch) to transduce signals induced by hedgehog protein. Binding of hedgehog protein to Ptch prevents normal inhibition by Ptch and Smo.
Basal cell carcinoma
Medulloblastoma
Nevoid basal cell carcinoma syndrome
Pancreatic cancer 
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