Hedgehog Signaling and Ptch1 Role
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What is the consequence of Ptch1 conditional knockout (KO) on SHH gene expression in astrocytes?

  • It inhibits the expression of essential morphogenetic genes.
  • It leads to the activation of the SHH pathway. (correct)
  • It results in downregulation of SMO expression.
  • It causes a decrease in astrocyte proliferation.

    • What specific role does Ptch1 play in the Hedgehog signaling pathway?

  • It is involved in the degradation of SHH proteins.
  • It acts as a repressor of the SHH pathway. (correct)
  • It serves as an activator of SHH genes.
  • It functions as a co-receptor alongside SMO.

    • Which of the following gene expression changes is NOT expected from Ptch1 KO in astrocytes?

  • Upregulation of SMO expression.
  • Disregulation of multiple genes involved in development.
  • Alterations in morphogenetic gene expression.
  • Increased expression of Ptch1 itself. (correct)

    • What types of cellular pathways are likely affected by the disregulation of gene expression following Ptch1 KO?

    <p>Morphogenetic and developmental pathways.</p> Signup and view all the answers

    In the context of the data presented, what criteria were used to identify significant gene expression changes in Ptch1cKO astrocytes?

    <p>p &lt; 0.01 and |log2FoldChange| &gt; 1.</p> Signup and view all the answers

    What is the molecular weight range of WNT proteins?

    <p>36 to 50 KDa</p> Signup and view all the answers

    Which modification is NOT characteristic of WNT proteins?

    <p>Phosphorylation</p> Signup and view all the answers

    What role does dishevelled play in WNT signaling?

    <p>Activation of the morphogenetic signal</p> Signup and view all the answers

    Which mechanism is NOT mentioned as a means of WNT transport?

    <p>Vesicular transport</p> Signup and view all the answers

    What is a known characteristic feature of WNT proteins?

    <p>Presence of at least one invariant cysteine</p> Signup and view all the answers

    What is the primary function of the WNT antagonist in embryonic development?

    <p>Facilitation of antero-posterior axis formation</p> Signup and view all the answers

    How many WNT proteins are known to exist in mammals?

    <p>19</p> Signup and view all the answers

    What type of diffusion is facilitated by a chaperone-like mechanism in WNT trafficking?

    <p>Facilitated diffusion</p> Signup and view all the answers

    Which of the following roles is NOT associated with the Hedgehog (HH) pathway?

    <p>Promotes apoptosis in adult tissues</p> Signup and view all the answers

    What is the primary function of Hedgehog (HH) ligands during embryonic development?

    <p>Regulating gene expression for body segmentation</p> Signup and view all the answers

    Which Hedgehog (HH) ligand is specifically known as Sonic Hedgehog?

    <p>SHH</p> Signup and view all the answers

    How many distinct mechanisms of secretion are associated with Hedgehog (HH) ligands?

    <p>Four</p> Signup and view all the answers

    The degradation of Hedgehog (HH) ligands occurs primarily through which cellular mechanism?

    <p>Proteasomal degradation</p> Signup and view all the answers

    Which of the following processes is NOT a known role of Hedgehog (HH) pathway in adult organisms?

    <p>Cell cycle arrest</p> Signup and view all the answers

    What is the first step in the biogenesis of Hedgehog (HH) ligands?

    <p>Translation of a 45 kDa precursor</p> Signup and view all the answers

    The study of which organism was crucial in the discovery of the Hedgehog (HH) pathway?

    <p>Drosophila melanogaster</p> Signup and view all the answers

    What is the primary consequence of dysregulated Hedgehog (HH) signaling in cells?

    <p>Increased cellular proliferation and tumor growth</p> Signup and view all the answers

    Which type of Hedgehog pathway activation is characterized by ligand dependency and an autocrine activation model?

    <p>Type II</p> Signup and view all the answers

    Type III of the Hedgehog pathway activation model involves which mechanism?

    <p>Ligand dependent and paracrine activation</p> Signup and view all the answers

    What characterizes Type IV activation of the Hedgehog pathway?

    <p>Aberrant activation in stem cells, either autocrine or paracrine</p> Signup and view all the answers

    Which type of activation does not depend on external ligand signaling?

    <p>Type I</p> Signup and view all the answers

    What happens when there is a mutation in the PTCH gene in a Gorlin patient?

    <p>The PTCH protein has altered functionality.</p> Signup and view all the answers

    Which role does a HH pathway activator play in relation to cancer?

    <p>It is a proto-oncogene.</p> Signup and view all the answers

    In a normal cell, how is PTCH function characterized?

    <p>Complete functional capacity at 100%.</p> Signup and view all the answers

    What is the functional consequence of PTCH loss of function in a Gorlin patient’s tumoral cell?

    <p>No functional PTCH protein is present.</p> Signup and view all the answers

    How is the role of a HH pathway inhibitor categorized in cancer biology?

    <p>It serves as a tumor suppressor.</p> Signup and view all the answers

    What can result from PTCH mutations alongside loss of heterozygosity (LOH) in Gorlin patients?

    <p>Complete loss of PTCH function leading to cancer.</p> Signup and view all the answers

    Which of the following accurately describes the outcome of 50% functional PTCH protein in cells?

    <p>Increased risk of cancer development.</p> Signup and view all the answers

    What is the overarching role of the Hedgehog pathway in tumor biology?

    <p>To contribute to oncogenesis depending on whether genes act as suppressors or activators.</p> Signup and view all the answers

    What happens to the function of PTCH in tumoral cells derived from Gorlin patients?

    <p>It shows complete loss of functional activity.</p> Signup and view all the answers

    For a patient with Gorlin syndrome, what is the consequence of inheriting a PTCH mutation?

    <p>They will have a significantly lower tumor suppressor capacity.</p> Signup and view all the answers

    What role does the Sonic HH morphogen play during embryogenesis?

    <p>Guides cell differentiation and tissue patterning</p> Signup and view all the answers

    Which of the following statements describes the function of the Ptch1 gene in the Hedgehog pathway?

    <p>Ptch1 represses SMO activity and inhibits GLI activation</p> Signup and view all the answers

    How does the LacZ-neo fusion gene affect the modified Ptch1 gene in the heterozygous mutant mice?

    <p>It introduces a beta-galactosidase reporter gene in place of part of the coding sequence</p> Signup and view all the answers

    What is the consequence of Smoothened (SMO) being inactive in the Hedgehog signaling pathway?

    <p>GLI proteins are ubiquitinated and degraded</p> Signup and view all the answers

    During which time frame does cortical development in mice reach completion?

    <p>By post-natal day 60</p> Signup and view all the answers

    Which of the following describes a possible method to visualize the expression of the LacZ reporter gene in mouse tissues?

    <p>Histochemical staining for beta-galactosidase activity</p> Signup and view all the answers

    How does the expression of Ptch1 vary during cortical development in the context of Shh signaling?

    <p>It is upregulated in the presence of Shh signaling</p> Signup and view all the answers

    What is the importance of spatial and temporal gradients of Sonic HH in tissue development?

    <p>They guide cells to their appropriate locations in embryonic development</p> Signup and view all the answers

    What effect does GLI activation have on gene transcription?

    <p>It promotes the transcription of target genes involved in development</p> Signup and view all the answers

    Study Notes

    Shared Signaling Pathways in Ontogenesis and Oncogenesis

    • Ontogenesis encompasses the formation and development of an organism, while oncogenesis is the formation of a tumor.
    • Some signaling pathways are shared between these two processes.

    Mechanisms of Activation of Proto-oncogenes

    • Proto-oncogenes are normal genes that regulate cell growth and division.
    • Mutations can activate proto-oncogenes, transforming them into oncogenes.
    • Activation mechanisms include:
      • Translocation or transposition: Movement of a gene to a new location.
      • Gene amplification: Increased copy number of a gene.
      • Point mutation: altering a single nucleotide within the gene sequence. This can lead to an oncogene.

    Mechanisms of Inactivation of Tumor Suppressor Genes

    • Tumor suppressor genes normally prevent uncontrolled cell growth.
    • Inactivation occurs through different mechanisms:
      • First event: A mutation or epigenetic change (either inherited or acquired).
      • Second event: A second mutation or epigenetic change. This eliminates or inactivates the function of the second allele of the tumor suppressor gene.

    Wnt Signaling Network

    • The Wnt signaling pathway is critical for cell development and tissue patterning.
    • The pathway is activated when Wnt protein binds to its receptor.
    • Activation leads to cell proliferation and differentiation.
    • Various components play a role in the Wnt pathway.

    Common Features of Wnt Proteins

    • Wnt proteins are secreted signaling molecules.
    • They contain multiple invariant cysteine residues.
    • Wnt proteins are generally secreted but not always highly soluble.
    • They are often glycosylated.
    • Wnt proteins are lipid modified, including palmitic acid and/or palmitoleic acid (prenylation).
    • They have a molecular weight between 36 and 50 kDa.

    Trafficking of Wnt Outside of the Cells

    • Wnt signaling molecules can be transported outside of cells by exosomes or lipoprotein particles.
    • Exosomes are small vesicles released from cells that carry various molecules, including Wnt proteins
    • Lipoprotein particles are complexes of proteins and lipids that carry signaling molecules, including Wnt.

    Facilitated Diffusion of Wnt

    • Wnt proteins can diffuse locally within tissues and across tissues, facilitated by Wnt-binding proteins, such as sFRP, or chaperone-like proteins.
    • Lateral diffusion plays a role in this process.
    • Wnt proteins bind to receptors on target cells.

    Cytoneme-mediated Wnt transport

    • Cytonemes are thin, cytoplasmic protrusions connecting cells, that can transport Wnt protein.
    • Cytonemes are formed by the polymerisation of actin.
    • Cytonemes are involved in cell-to-cell communication during development.

    Gene Gradient Interplay for Antero-Posterior Axis Formation and Liver Development

    • Genes are essential for the formation and development of the antero-posterior axis for embryonic and liver development
    • Wnt-β-catenin, FGF, BMP play key roles in liver cell formation and development.

    Gene Gradient Interplay for the Intestinal Crypt Development and Maintenance

    • BMP (bone morphogenetic protein).
    • Wnt is essential for the development and maintenance of intestinal crypts.
    • Notch signaling impacts the development and maintenance of intestinal crypt.

    Canonical and Non-canonical Wnt Pathways

    • List of genes involved in canonical and non-canonical Wnt pathways

    Oncogenesis Activity 4

    • Sanger sequence for the mAPC gene.
    • Different heptad, armadillo, and SAMP repeats are present for the gene's function.

    Different Germline Mutations in APC Influence Polyps Phenotype in Mouse Models

    • Germline mutations in APC influence the phenotype of polyps in mouse models.
    • Various phenotypes are presented due to the different locations and types of mutations.

    Step-wise Tumorigenesis in Colorectal Cancer

    • Stepwise tumorigenesis leads from normal mucosa to aberrant crypt foci and to an adenoma and finally to colorectal cancer.

    Hedgehog Pathway and Cancer

    • The Hedgehog (HH) pathway is critical for development and implicated in many cancers, impacting many functions.
      • Pathway components have both oncogenic and tumor suppressive roles, depending on their function.

    Hedgehog (HH) pathway

    • The Hedgehog (HH) pathway is a crucial signaling pathway involved in development, embryonic cell differentiation, body segmentation, organogenesis, and the regulation of adult stem cells.
    • The Hedgehog pathway is related to the study of Drosophila.

    Hedgehog (HH) Ligands

    • There are three HH homologous in mammals: Desert Hedgehog, Indian Hedgehog, and Sonic Hedgehog (SHH).
    • SHH is a key ligand in the HH pathway and plays an important role in development.

    Hedgehog (HH) Ligands Biogenesis

    • HH ligands are encoded by genes.
    • The mature HH Ligands are 45 kDa precursor molecules that undergo multiple post-translational modifications in the endoplasmic reticulum.

    Hedgehog (HH) Ligands Secretion

    • There are four different mechanisms of secretion: soluble oligomer, apolipoprotein, exosome, and lipoproteins.

    Hedgehog (HH) Pathway Signaling

    • The HH Pathway components interact with one another forming different protein complexes.
    • These different proteins are involved in different stages in the process.

    Ptch1 / SMO Interaction

    • PTCH1 functions as a receptor for the HH pathway and SMO and is a regulator of the pathway.
    • SMO activity is essential for the function of the pathway.

    GLI Activation

    • GLI proteins are transcription factors that regulate gene expression in the Hedgehog (HH) pathway.
    • SMO regulation of the GLI proteins is essential for the functionality of the pathway.

    Hedgehog (HH) Pathway and Development

    • Sonic Hedgehog (SHH) is a major morphogen in embryogenesis.
    • Spatial and temporal gradients of SHH guide cell during embryonic development.

    Activity 5: Astrocyte-Neuron Crosstalk Through Hedgehog Signaling

    • Ptch1 plays a crucial role in Hedgehog (HH) signaling in the developing cortex.
    • The presence of a beta-galactosidase enzyme in the region where a mutant Ptch1-lacZ gene has been inserted is identified
    • The temporal and cell type-specific expression of Ptch1 is important.

    Ptch1 gene

    • This gene is vital in the Hedgehog (HH) pathway and is structurally modified in the cases studies.

    Cortical layers

    • Cortical layers are different layers in the brain cortex.
    • The cells in layers are vital for different functions of the brain.

    Hedgehog (HH) Pathway and Development

    • Cell density varies in cortical layers during the first 60 days of mouse life.
    • The highest cell density is present in layers II/III and IV at P5.
    • The lowest cell density is present in layers II/III and IV at P60.

    Hedgehog (HH) Pathway and Development Activity 6

    • BxPC3 cell is the primary cancer cell line that has been used for experimentation and study.
    • Cyclopamine is an inhibitor of HH pathway, which is a DNA intercalator that inhibits the DNA replication and slows down the cell-cycle.
    • Cyclopamine increases cell apoptosis and decrease cell proliferation.

    HH Pathway: Therapeutics

    • Cyclopamine is the first HH pathway inhibitor identified, derived from Veratum californicum
    • It blocks SMO protein, causing it to become inactive.
    • However, cyclopamine has low bioavailability, short half-life, and chemical instability

    HH Pathway: Therapeutics

    • Novel SMO antagonists based on cyclopamine have been developed.
    • These are more potent and have improved bioavailability and stability.
    • Glasdegib, one such SMO antagonist, was approved.

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    Lecture 9 UE TBMC Cancer Biology PDF

    Description

    This quiz delves into the consequences of conditional knockout of Ptch1 on SHH gene expression in astrocytes, exploring its specific role in the Hedgehog signaling pathway. Participants will identify expected gene expression changes and discuss the cellular pathways affected by this knockout. Additionally, criteria for significant gene expression changes in Ptch1cKO astrocytes will be reviewed.

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