Name: hedgehog signaling in growth and disease
Uploaded: 2021-04-07T12:11:59.000Z
Duration: 2 min 33 s
Channel: JoVE

Hedgehog signaling is a conserved signaling pathway that regulates cell growth during embryonic development and tissue homeostasis, in invertebrates as well as vertebrates.
Unrestricted Hedgehog signaling can lead to several human developmental abnormalities and diseases including, cancers.
There are three key players in the Hedgehog signaling pathway.
The lipid-modified active Hedgehog ligand that acts as a local mediator, a transmembrane protein called Patched that acts as a receptor for the Hedgehog ligand and a transcription regulator called Cubitus Interruptus or Ci that acts as the primary effector molecule.
The Ci can exist in two different forms- an intact protein form, which acts as a transcriptional activator and a cleaved form called Ci75 which acts as a transcriptional repressor for various Hedgehog-responsive genes.
The intact Ci exists in association with a multiprotein complex bound to microtubules that consist of Fused kinase and Costal-2, a kinesin-like protein.
In the absence of Hedgehog ligand, the Patched protein continuously represses the activity of Smoothened protein - a transmembrane protein present on internal cell vesicles.
This elicits the processing of C

hedgehog signaling pathway

Hedgehog Signaling Pathway

The Hedgehog gene (Hh) was first discovered due to its control of the growth of disorganized, hair-like bristles phenotype in Drosophila, much like hedgehog spines. Hh plays a crucial role in the development of organs and the maintenance of homeostasis in both invertebrates and vertebrates. However, while Drosophila has only one Hh protein, mammals have multiple functional Hedgehog proteins - Sonic (Shh), Desert (Dhh), and Indian Hedgehog (Ihh). All of these homologous proteins have adapted to perform specialized functions in different developmental processes in mammals. Additionally, unlike in invertebrate Hh signaling, mammalian Hedgehog signaling is also reliant upon a microtubule-based organelle called the primary cilium that is present on the cell surface of most vertebrate cells.
<h4>The Hedgehog Signaling Mechanism</h4>
The Hedgehog gene encodes for the Hedgehog precursor protein, which undergoes significant posttranslational modifications inside the endoplasmic reticulum. These lipid modifications of the Hedgehog protein play an essential role in the secretion of the active Hedgehog ligand from the signaling cell and its migration to the target cells. In the absence of active Hedgehog ligand, the Patched protein present on the target cell surface is the primary inhibitor of the downstream Hedgehog signaling. However, when the active Hedgehog ligand binds to the Patched protein, another transmembrane protein called Smoothened translocates to the cell surface. The Smoothened protein is then able to interrupt the activity of a multiprotein microtubule-associated complex in its degradation of Cubitus Interruptus. Cubitus Interruptus is the primary transcriptional activator in the Hh signaling pathway and subsequently translocates to the nucleus to turn on the expression of Hh target genes.
<h4>Functions and Associated Diseases</h4>
Hh signaling is crucial for organ development, and any disruptions to Hh during embryogenesis can lead to severe developmental abnormalities. Additionally, Hh signaling is essential for stem cell regeneration, which is responsible for the maintenance and regeneration of adult tissues. Abnormalities in the Hh signaling pathway can, therefore, lead to certain types of cancer, including pancreas, lung, prostate, breast, and brain tumors. Because of this, the Hh gene and signaling pathway is a valid therapeutic target for the pharmaceutical industry.

The Hedgehog gene (Hh) was first discovered due to its control of the growth of disorganized, hair-like bristles phenotype in Drosophila, much like ...

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JoVE Core

Molecular Biology

Unit 2

Cell Signaling Pathways

KEY TERMS AND CONCEPTS

hedgehog signaling in growth and disease

Hedgehog signaling helps guide organ development and tissue balance in both invertebrates and vertebrates. The Hedgehog gene was first identified because it affected the growth of disorganized, hair-like bristles in Drosophila, which looked like hedgehog spines. In mammals, the pathway includes Sonic Hedgehog (Shh), Desert Hedgehog (Dhh), and Indian Hedgehog (Ihh), which each carry out specialized roles in development.

Mammalian Hedgehog signaling also depends on the primary cilium, a microtubule-based organelle on the surface of most vertebrate cells. This is different from invertebrate Hedgehog signaling. The Hedgehog precursor protein is made from the Hh gene and is modified inside the endoplasmic reticulum. These lipid changes are important for releasing the active Hedgehog ligand and helping it move to target cells.

When no active Hedgehog ligand is present, Patched on the target cell surface blocks downstream signaling. When the ligand binds Patched, Smoothened moves to the cell surface. Smoothened then stops a microtubule-associated complex from breaking down Cubitus Interruptus, the main transcriptional activator in the pathway. Cubitus Interruptus enters the nucleus and turns on Hedgehog target genes.

Hedgehog signaling is important during embryonic development, and disruptions can cause serious developmental abnormalities. It also supports stem cell regeneration, which helps maintain and renew adult tissues. When the pathway becomes abnormal, it can contribute to cancers of the pancreas, lung, prostate, breast, and brain. Because of these links, the Hedgehog pathway is also an important target for drug development.

Hedgehog Signaling in Growth and Disease

notch signaling pathway

Notch Cell Communication and Gene Control

Notch signaling is a conserved cell-to-cell communication pathway in animals. It is unusual because the Notch protein acts as both the receptor and the main signaling molecule. The pathway was first linked to a mutant wing shape in Drosophila melanogaster, where changes in the Notch gene caused a serrated, or "notched," wing margin. The Notch gene was later shown, in 1985, to encode a transmembrane surface receptor. Signaling starts when the Notch receptor on one cell directly binds the Delta...

canonical wnt signaling pathway

Wnt Signals in Development and Disease

Wnt signaling helps cells communicate during development and in adult tissues. The Wnt proteins were first discovered nearly four decades ago in genetic studies of body pattern defects in Drosophila. One gene was named wingless, or wg, because of the fly phenotype it caused. Around the same time, Harold Varmus found that a murine tumor virus activated the mammalian wg homolog, Int-1, and this activity led to tumor formation in mice. The gene family was later called Wnt, a name built from...

Hedgehog signaling helps guide organ development and tissue balance in both invertebrates and vertebrates. The Hedgehog gene was first identified because it affected the growth of disorganized, hair-like bristles in Drosophila, which looked like hedgehog spines. In mammals, the pathway includes Sonic Hedgehog (Shh), Desert Hedgehog (Dhh), and Indian Hedgehog (Ihh), which each carry out specialized roles in development. Mammalian Hedgehog signaling also depends on the primary cilium, a...

nf-&#954;b-dependent signaling pathway

NF-κB in Immune Defense and Disease

NF-κB is a transcription factor that helps control immune defense and inflammation in animals. It was discovered in 1986 in the lab of Nobel laureate Professor David Baltimore because of its interaction with the immunoglobulin light chain enhancer in B-cells. Since then, researchers have shown that NF-κB regulates the expression of more than 100 genes. Many of the genes controlled by NF-κB support innate and adaptive immune responses. They also help drive inflammatory responses. In this way,...

internal receptors

Internal Receptors and Hormone Signals

Internal receptors are proteins inside a cell that bind signaling molecules. These receptors help certain hormones send messages after they pass through the cell membrane. Because the receptor is internal, the signal acts from within the cell rather than at the surface. Many internal receptors respond to steroid hormones. These hormones can cross the membrane and reach the receptor inside the cell. Once the hormone binds, the receptor can help trigger a response that changes cell activity. <br...

circadian rhythms and gene regulation

Light Control of the Biological Clock

Light helps control the biological clock by shaping circadian rhythms. These 24-hour cycles affect how cells, body systems, and behavior stay in sync with day and night. In animals, this timing system helps regulate complex physiology. The study of circadian rhythm began in 1935, when German zoologists Hans Kalmus and Erwin Bünning found it in Drosophila melanogaster, the fruit fly. The molecular basis stayed unclear for decades. In 1984, Jeffrey C. Hall, Michael Rosbash, and Michael W. Young...

what is cell signaling?

Cell Signaling in Cell Communication

Cell signaling is a key part of cell communication. It helps cells send, receive, and respond to signals so they can work together. A signal starts when a cell releases a molecule. Another cell detects that molecule with a receptor, which is a protein that binds the signal. This binding begins a signaling pathway inside the cell. The pathway carries the message through the cell in a process called signal transduction. In the end, the cell produces a response. That response can change cell...

autocrine signaling

Autocrine Cell Communication

Autocrine cell communication is a signaling process in which a cell sends a message to itself. In this pathway, the cell releases a signaling molecule and also has receptors that can detect that same molecule. This makes the cell both the sender and the receiver. Autocrine signaling is common in cell communication and is often grouped with cytokine signaling. Cytokines are small signaling proteins that help cells communicate, especially in immune responses and growth control. In autocrine...

paracrine signaling

Local Cell Communication in Tissues

Paracrine signaling is a form of local cell communication in tissues. In this process, one cell releases chemical signals that affect nearby target cells. Because the signal stays close to where it is made, paracrine signaling helps cells coordinate responses within a limited area. These signals do not travel far through the body. Instead, they move through the space around neighboring cells and bind to specific receptors on target cells. This nearby action makes paracrine signaling different...

endocrine signaling

Hormones in Endocrine Signaling

Endocrine signaling uses hormones to send messages through the body. These signals travel through the bloodstream from one cell or gland to another target cell. The target cell responds only if it has the right receptor to detect the hormone. This type of cell communication helps coordinate many body functions at a distance. Because the signal moves through the blood, the source and the target do not need to be close together. Endocrine signaling is a key way cells regulate activity in other...

what are second messengers?

Cell Signals and Second Messengers

Second messengers are small molecules that help cells pass along signals after a receptor is activated. They carry the message inside the cell and help start a response to the outside signal. This signaling step is important in cell communication. It helps the signal move from the cell membrane to targets deeper inside the cell. Second messengers make that relay possible and help the cell respond in a controlled way. Common second messengers include cyclic AMP, calcium ions, and inositol...

intracellular signaling cascades

Cell Signaling Cascades Inside Cells

Cell signaling cascades inside cells relay messages from one molecule to the next. These pathways help a cell respond to a signal in a controlled way. The signal is often carried through a series of steps, which can amplify the original message. A signaling cascade may involve a receptor at the cell surface and molecules inside the cell that pass the message along. Each step can trigger the next step in the chain. This makes the response specific and allows the cell to act on the signal at the...

g-protein coupled receptors

G-protein Receptors in Cell Signaling

G-protein coupled receptors help cells receive and pass along signals. These membrane receptors sit in the cell membrane and respond when a ligand binds to them. A ligand is a molecule that fits and attaches to a receptor. When a ligand binds, the receptor changes shape. That shape change activates a G protein inside the cell. The G protein then helps start the signal inside the cell. These receptors are important because they connect outside signals to inside responses. They are a major part...

enzyme-linked receptors

How Enzyme-Linked Receptors Signal

Enzyme-linked receptors help cells respond to signals outside the cell. They are a major class of cell-surface receptors, and they work by triggering enzyme activity after a signal binds. Many enzyme-linked receptors are receptor tyrosine kinases. When a signaling molecule binds, the receptor changes shape and activates its enzyme side. This starts a signaling step inside the cell that can affect cell behavior. These receptors are important in cell communication. They help carry messages from...

non-canonical wnt signaling pathways

Wnt Pathways That Guide Cell Position

Wnt signaling helps guide early embryonic development and later life processes in animals. It is controlled by Wnt proteins, which can trigger different intracellular pathways depending on which receptors and co-receptors they bind. These signals support organ formation in the embryo and help maintain neuronal and blood stem cells. The non-canonical Wnt pathways are the β-catenin independent routes. They are more diverse and less well characterized than the canonical Wnt/β-catenin pathway. Two...

key terms and concepts

Learn how Hedgehog signaling guides development, works through Patched and Smoothened, and why pathway errors can lead to birth defects and cancer.

Hedgehog Signaling in Growth and Disease | JoVE K12

molecular biology

JoVE Core Molecular Biology showcases the molecular processes of the cell through clear and concise animated video lessons. Additionally, in scientist-in-action videos, these concepts' application is demonstrated through real experiments in modern laboratories.

Hedgehog Signaling in Growth and Disease

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