1.4: Major signaling pathways in developmental biology

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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 development^5,6. 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. These signal transduction pathways act as switches for Gene Regulatory Networks which they turn on using different mechanisms.

**Figure 1: Major developmental signaling pathways** by Ajna Rivera and Kristina Vu. An editable svg file of this figure can be downloaded at https://scholarlycommons.pacific.edu/open-images/20/

Two main factors affect which signaling pathway is used for patterning and specification.

1. 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.

2. 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.

Getting to know the pathways

Descriptions of the Notch, Wnt and Hedgehog pathways can be found at this link from Molecular Biology of the Cell. 4th edition:

https://www.ncbi.nlm.nih.gov/books/NBK26918/

The Ras/MAP kinase pathways use receptor tyrosine kinases. This category of pathway is described here.