What are some examples of cell signals?

Cell signaling is one of my absolute favorite topics in molecular biology. In fact, a lecture on cell signaling during my sophomore year of college was the reason why I decided to declare a molecular biology major with a concentration in cell and developmental biology.

Cell signaling is a specific type of cell-cell interaction where cells communicate with one another through the action of ligands from the signaling cells and impacting the receptor on the target cells. Ligands can be a variety of different types of small molecules. One can think of ligands as like a key that binds very specifically to one type of receptor (in this analogy, the receptor is like a lock for the key). The result of ligand binding to the receptor is a change in cellular behavior, typically as the result of changes in gene expression.

In this Common questions in molecular biology blog post, I explore two types of paracrine signaling, or of nearby cell signaling pathways, namely Hedgehog and Notch signaling. Then I’ll discuss one type of endocrine signaling, or signaling across distances, called nuclear hormone receptor signaling. Throughout I’ll highlight how single-cell sequencing and NanoString’s CosMx™ Spatial Molecular Imager provide important insights into the function of each of these types of signaling modalities.

What is Hedgehog signaling?

Hedgehog signaling is a type of paracrine (local area) signaling that controls a wide variety of processes during embryonic development. For example, Hedgehog signaling is important for organogenesis and pattern formation. In adults, Hedgehog signaling is also important for regeneration and homeostasis. Dysfunction of Hedgehog signaling is implicated in cancer.

One of the most well known examples of hedgehog signaling is in pattern formation, particularly in appendages such as the hands, feet, or in arguably the most famous examples, paws. Hedgehog protein is expressed in a gradient. Depending on how close developing cells are to the source of protein dictates what structures form. In this case, if you look at the pattern of your hand, you have a pinky on one side and a thumb on the other.

Defects in Hedgehog signaling can cause a variety of birth defects, among them the formation of additional digits, a condition known as polydactyly. The most famous sufferers of polydactyly are probably the so-called “Hemingway Cats” of Key West, Florida. Scientists believe that shipping traffic first introduced a polydactyl cat to the island many years ago. The descendants of this cat included felines owned by Hemingway himself, many of whom still reside at the Hemingway house in Key West.

What is Notch signaling?

Like Hedgehog signaling, Notch signaling is a type of paracrine signaling. It also has important roles in development as well as implications for cancer development. Unlike other ligands, the ligand for Notch, called Delta, is not soluble in the cell. Rather, Delta is found on an adjacent cell. Therefore, for successful transduction of the Notch signal, cells must be at the perfect spatial orientation to one another, so that the Delta ligand can properly interact with the Notch receptor.

In addition to its roles in the embryonic development of a wide variety of tissues, from the nervous system to bone, aberrations in Notch signaling are also implicated in a variety of cancers. For example, loss of Notch signaling is one of the major forces driving the development of bladder cancer.

Given the importance of spatial relationships in functionality of Notch signaling, spatially-resolved single-cell sequencing using NanoString’s CosMx Spatial Molecular Imager could provide important insights into how aberrations in Notch signaling lead to development of cancer. With this knowledge in hand, researchers could also begin to develop and test interventions that replicate normal Notch signaling in cancerous tissues as a potential treatment modality.

What is nuclear hormone receptor signaling?

Nuclear hormone receptor signaling is a type of endocrine signaling that is responsible for a wide diversity of cell signaling events. Although there are several classes of nuclear hormone receptors, arguably the most well known group are the steroid hormone receptors. This includes the glucocorticoid, androgen, estrogen, progesterone, and mineralocorticoid receptors. These receptors are typically found inside the cell, and once the ligand diffuses into the cell and binds to them, act as transcription factors.

Steroid hormone receptors mediate a wide variety of normal biological functions. As such, aberrations in nuclear hormone receptor signaling are implicated in a wide variety of diseases, from cancer to depression. For example, abnormal signaling via the estrogen receptor is implicated in breast cancer progression.

In the case of the glucocorticoid receptor (GR), it is essential for regulating the body’s response to stress. The stress response begins in the brain with the hypothalamus. The hypothalamus acts as the link between the nervous and endocrine systems. In response to some outside stressor, the hypothalamus signals to the pituitary gland, which then releases a signal into the bloodstream that causes the adrenal glands to release cortisol, the ligand for GR. GR is located in all cells, and its activation causes changes in gene expression. In the context of a stress response, it enables the body to effectively respond to the stressor. GR also stimulates the transcription of genes that act as part of a negative feedback loop to shut down the response. Overactivation of this pathway is implicated a variety of neuropsychiatric diseases, including anxiety, depression, and post-traumatic stress disorder.

Summary

So much of biology relies on cell signals occurring at the right time, the right place, and to the right amount. Studying cell-cell interactions like cell signaling using single-cell sequencing and NanoString’s CosMx Spatial Molecular Imager provide unprecedented insight into a variety of biological functions, including embryonic development, regeneration, and the molecular basis of cancer. Single-cell sequencing is particularly important considering the spatial nature of many of these interactions to get proper functioning, such as the spatial relationship between the Notch receptor and ligand.

The CosMx™ SMI and decoder probes are not offered and/or delivered to the Federal Republic of Germany for use in the Federal Republic of Germany for the detection of cellular RNA, messenger RNA, microRNA, ribosomal RNA and any combinations thereof in a method used in fluorescence in situ hybridization for detecting a plurality of analytes in a sample without the consent of the President and Fellows of Harvard College (Harvard Corporation) as owner of the German part of EP 2 794 928 B1. The use for the detection of cellular RNA, messenger RNA, microRNA, ribosomal RNA and any combinations thereof is prohibited without the consent of the President and Fellows of Harvard College (Harvard Corporation).