Cell-cell communication: Signal transduction pathways
Signal transduction pathways couple external signals to changes in gene expression within a cell. That is, an external signal triggers a cascade of biochemical changes in the cell resulting in higher or lower transcription of a set of genes. Fewer than a dozen major signal transduction pathways commonly regulate animal development5,6. Here, we will focus on four of these named after their receptor or ligand: Notch, Hedgehog (Hh), TGF-b (also called Dpp or BMP), and Wnt (Figure 3). These signal transduction pathways act as switches for Gene Regulatory Networks (discussed below) which they turn on using different mechanisms. Two main factors affect what types of patterning and specification processes a particular Signal Transduction Pathway is good for.
Figure 4: Some common signal transduction pathways in development. Illustrated here are the Notch, BMP (aka DPP or TGFb), Hedgehog (Hh), and Wnt pathways. Ligands are blue, receptors are green, intracellular pathway members are pink and orange, local activators/repressors are red. In the Notch pathway, Notch is both the recepter and the intracellular pathway member after it is cleaved (Notch Intracellular Domain or NICD). Note that in the Hh pathway, there are multiple versions of Cubitus Interruptus (Ci aka Gli). These can be Repressive (R) or Active (A). Figure by Kristina Vu.
First, how is the signal communicated? Does it use a long-range ligand (paracrine signaling), does it require cell-to-cell contact (juxtacrine signaling), or does the ligand act on the same cell it was secreted from (autocrine signaling)? Long-range paracrine pathways, like TGF-b and Wnt are great at forming gradients across a large tissue and are often used as early morphogens patterning body axes or multiple cell types across a tissue. Short-range paracrine pathways, like Hh, often act as morphogens on a smaller scale - fine-tuning regionalization patterns. Other factors modify the signaling range of these ligands, for example the amount of ligand secreted, neutralization by extracellular matrix proteins, the number of responsive cells, and whether responsive cells are expressing inhibitors or coactivators of the target genes6. Juxtacrine signals, like the Notch pathway, involve the association of two membrane-bound receptors. In the case of Notch, this is typically a Delta/Serrate/Lag-12 (DSL)-class ligand and a full length glycosylated Notch protein. The Notch pathway is often used in on/off cell-fate decisions, famously in lateral-inhibition where an "on" signal in one cell triggers an "off" signal in all the surrounding cells.
The second important factor governing the utility of a Signal Transduction Pathway is its regulation. Most pathways can be regulated to some extent by their downstream target genes either through negative or positive feedback. In negative feedback the downstream target genes eventually turn the pathway off. For example, a signaling pathway could increase the transcription of a pathway inhibitor. In positive feedback they downstream targets keep the pathway on. For example, a signaling pathway could increase the transcription of its own receptor. Thus, negative feedback is good for promoting a transient one-time signal, while positive feedback converts a transient signal into a permanent cell-fate decision. Pathways can also be regulated by each other and their output can be modified by local transcription factors, which can differ among cell types. This topic is covered more extensively in Three habits of highly effective signaling pathways. by Borolo and Posakony.
Within the cell: Gene regulatory networks
In the early 2000s, Eric Davidson and Isabelle Peter wrote a series of papers proposing a philosophical framework for understanding Gene Regulatory Networks (GRNs). In 2011 they wrote a seminal paper on the evolution of these networks. They defined three basic types of core genetic interaction that are used to specify cell-types:
- kernels: these are evolutionarily inflexible interactions that specify a body part.
- batteries: These are involved in cell or tissue differentiation and are more flexible evolutionarily than kernels.
- plug-ins: these are small sub-circuits that get used in many different developmental contexts7.
As a mother to Lego enthusiasts, I use Lego kits as an analogy to understand this. A kernel would be specialized pieces that go together, like a pair of wheels and an axle. They specify a particular function and are inflexible in their interaction - one wheel must be snapped onto each side of the axle to make it useful. A "battery" is more flexible but still usually used for a similar set of purposes. An example of this would be a literal battery pack in a Lego kit - it is used to power movement but is flexible in that it can power many types of constructions. A plug-in is similar to standard bricks, these can be used to build whatever cuboid objects your imagination suggests In order to make fancy constructions, however, you also require kernels and batteries.
How do we link these types of interactions to a developing embryo? Peter and Davidson conceive of animal development as being alternating steps of patterning and specification7. Patterning is dividing up a body or a set of tissues into smaller parts. Specification is a fate choice for the cell or tissue that was patterned. In this conception, the body axes and germ layers are first defined using body patterning genetic networks. Next, each section of the body is specified: neuroectoderm, gut, pharyngeal arches (in chordates), circulatory system, etc. Then, another round of patterning of these specified units occurs - each body part now gets patterned along its own axes. For example, the tips of the fingers vs an elbow or the anterior vs. the posterior of the heart (Figure 5).8
Figure 5: Patterning and Specification