Cell-to-cell signaling is essential for induction, for conference of competency to respond, and for crosstalk between inducing and responding cells. These lines of communication are established by paracrine interactions, whereby proteins synthesized by one cell diffuse over short distances to interact with other cells, or by juxtacrine interactions, which do not involve diffusable proteins. The diffusable proteins responsible for paracrine signaling are called paracrine factors or growth and differentiation factors (GDFs).

Signal Transduction Pathways

Paracrine Signaling

Paracrine factors act by signal transduction pathways either by activating a pathway directly or by blocking the activity of an inhibitor of a pathway (inhibiting an inhibitor, as is the case with hedgehog signaling). Signal transduction pathways include a signaling molecule (the ligand) and a receptor (Fig. 1). The receptor spans the cell membrane and has an extracellular domain (the ligand-binding region), a transmembrane domain, and a cytoplasmic domain. When a ligand binds its receptor, it in duces a conformational change in the receptor that activates its cytoplasmic domain. Usually, the result of this activation is to confer enzymatic activity to the receptor, and most often, this activity is a kinase that can phosphorylate other proteins using ATP as a substrate. In turn, phosphorylation activates these proteins to phosphorylate additional proteins, and thus, a cascade of protein interactions is established that ultimately activates a transcription factor. This transcription factor then activates or inhibits gene expression. The pathways are numerous and complex and in some cases are characterized by one protein inhibiting another that in turn activates another protein (much like the situation with hedgehog signaling).

Fig1. Drawing of a typical signal transduction pathway involving a ligand and its receptor. Activation of the receptor is conferred by binding to the ligand. Typically, the activation is enzymatic involving a tyrosine kinase, although other enzymes may be employed. Ultimately, kinase activity results in a phosphorylation cascade of several proteins that activates a transcription factor for regulating gene expression.

Juxtacrine Signaling

 Juxtacrine signaling is mediated through signal transduction pathways as well but does not involve diffusable factors. Instead, there are three ways juxtacrine signaling occurs: (1) A protein on one cell surface interacts with a receptor on an adjacent cell in a process analogous to paracrine signaling (Fig. 1). The Notch pathway represents an example of this type of signaling . (2) Ligands in the extracellular matrix secreted by one cell interact with their receptors on neighboring cells. The extracellular matrix is the milieu in which cells reside. This milieu consists of large molecules secreted by cells including collagen, proteoglycans (chondroitin sulfates, hyaluronic acid, etc.), and glycoproteins, such as fibronectin and laminin. These molecules provide a substrate for cells on which they can anchor or migrate. For example, laminin and type IV collagen are components of the basal lamina for epithelial cell attachment, and fibronectin molecules form scaffolds for cell migration. Receptors that link extracellular molecules such as fibronectin and laminin to cells are called integrins. These receptors “integrate” matrix molecules with a cell’s cytoskeletal machinery (e.g., actin microfilaments), thereby creating the ability to migrate along matrix scaffolding by using contractile proteins, such as actin.

Also, integrins can induce gene expression and regulate differentiation as in the case of chondrocytes that must be linked to the matrix to form cartilage. (3) There is direct transmission of signals from one cell to another by gap junctions. These junctions occur as channels between cells through which small molecules and ions can pass. Such communication is important in tightly connected cells like epithelia of the gut and neural tube because they allow these cells to act in concert. The junctions themselves are made of connexin proteins that form a channel, and these channels are “connected” between adjacent cells.

It is important to note that there is a great amount of redundancy built into the process of signal transduction. For example, paracrine signaling molecules often have many family members such that other genes in the family may compensate for the loss of one of their counterparts. Thus, the loss of function of a signaling protein through a gene mutation does not necessarily result in abnormal development or death. In addition, there is cross talk between pathways, such that they are intimately interconnected. These connections provide numerous additional sites to regulate signaling.

Paracrine Signaling Factors

 There is a large number of paracrine signaling factors acting as ligands, which are also called GDFs. Most are grouped into four families, and members of these same families are used repeatedly to regulate development and differentiation of organ systems. Furthermore, the same GDFs regulate organ development throughout the animal kingdom from Drosophila to humans. The four groups of GDFs include the fibroblast growth factor (FGF), WNT, hedgehog, and transforming growth factor-B (TGF-B) families. Each family of GDFs interacts with its own family of receptors, and these receptors are as important as the signal molecules themselves in determining the outcome of a signal.

Fibroblast Growth Factors

 Originally named because they stimulate the growth of fibroblasts in culture, there are now approximately two dozen FGF genes that have been identified, and they can produce hundreds of protein isoforms by altering their RNA splicing or their initiation codons. FGF proteins produced by these genes activate a collection of tyrosine receptor kinases called fibroblast growth factor receptors (FGFRs). In turn, these receptors activate various signaling pathways. FGFs are particularly important for angiogenesis, axon growth, and mesoderm differentiation. Although there is redundancy in the family, such that FGFs can sometimes substitute for one an other, individual FGFs may be responsible for specific developmental events. For example, FGF8 is important for development of the limbs and parts of the brain.

Hedgehog Proteins

The hedgehog gene was named because it coded for a pattern of bristles on the leg of Drosophila that resembled the shape of a hedgehog. In mammals, there are three hedgehog genes: desert, Indian, and sonic hedgehog. Sonic hedgehog (SHH) is involved in a multitude of developmental events .

WNT Proteins  

There are at least 15 different WNT genes that are related to the segment polarity gene, wing less in Drosophila. Their receptors are members of the frizzled family of proteins. WNT proteins are involved in regulating limb patterning, midbrain development, and some aspects of so mite and urogenital differentiation among other actions.

The TGF-β Superfamily

The TGF-β superfamily has more than 30 mem bers and includes the TGF-Bs, the bone morphogenetic proteins (BMPs), the activin family, the miillerian inhibiting factor (MIF, anti-miillerian hormone), and others. The first member of the family, TGF-BI, was isolated from virally transformed cells. TGF-B members are important for extracellular matrix formation and epithelial branching that occurs in lung, kidney, and salivary gland development. The BMP family induces bone formation and is involved in regulating cell division, cell death (apoptosis), and cell migration among other functions.

Other Paracrine Signaling Molecules

Another group of paracrine signaling molecules important during development are neurotransmitters, including serotonin, y-amino butyric acid (GABA), epinephrine, and norepinephrine, that act as ligands and bind to receptors just as proteins do. These molecules are not just transmitters for neurons; they also provide important signals for embryological development. For example, serotonin (5-HT) acts as a ligand for a large number of receptors, most of which are G protein—coupled receptors. Acting through these receptors, 5-HT regulates a variety of cellular functions, including cell proliferation and migration, and is important for establishing laterality, gastrulation, heart development, and other processes during early stages of differentiation. Norepinephrine also acts through receptors and appears to play a role in apoptosis (programmed cell death) in the interdigital spaces and in other cell types.

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