Related Experiment Video
Updated: Jan 6, 2026
10:51
Isolation and Culture of Primary Mouse Keratinocytes from Neonatal and Adult Mouse Skin
Published on: July 14, 2017
32.7K
The RIPK4-IRF6 signalling axis safeguards epidermal differentiation and barrier function.
Nina Oberbeck1, Victoria C Pham2, Joshua D Webster3
1Department of Physiological Chemistry, Genentech, South San Francisco, CA, USA.
Nature
|October 4, 2019
Summary
The kinase RIPK4 and transcription factor IRF6 are crucial for epidermal barrier function. Their coordinated action ensures proper skin development, and defects lead to severe developmental abnormalities.
Area of Science:
- Developmental Biology
- Molecular Biology
- Genetics
Background:
- Mammalian epidermis integrity relies on stem cell proliferation and differentiation.
- Mutations in RIPK4 and IRF6 cause developmental syndromes with epidermal defects.
- The precise roles of RIPK4 and IRF6 in epidermal differentiation are not fully understood.
Purpose of the Study:
- To elucidate the mechanisms by which RIPK4 and IRF6 regulate epidermal differentiation.
- To define the transcriptional programs controlled by IRF6 in the developing epidermis.
- To understand the functional consequences of IRF6 deficiency on epidermal barrier formation.
Main Methods:
- Utilized RNA sequencing (RNA-seq), ChIP-seq, and ATAC-seq on wild-type and IRF6-deficient mouse embryos.
- Investigated the kinase activity requirement for RIPK4 in development.
- Analyzed IRF6 phosphorylation sites critical for its activation.
Main Results:
- RIPK4 kinase activity is essential for mouse development.
- RIPK4 and IRF6 regulate common biological processes in the epidermis.
- IRF6 phosphorylation at Ser413 and Ser424 primes it for activation.
- IRF6 deficiency impairs genes involved in lipid metabolism and tight junction formation.
- Irf6-/- mice exhibit abnormal stratum corneum lipid composition and epidermal barrier defects.
Conclusions:
- RIPK4 and IRF6 are key regulators of epidermal integrity through coordinated control of differentiation.
- Defects in the RIPK4-IRF6 axis explain developmental syndromes affecting orofacial, skin, and genital development.
- Phosphorylation of IRF6 is a critical step in its activation pathway during epidermal development.
Related Concept Videos
01:22Role of Ephrin-Eph Signalling in Intestinal Stem Cell Renewal
2.6K
Erythropoietin-producing hepatocellular carcinoma receptor (Eph) and its ligand, Eph receptor-interacting protein (Ephrin) were first discovered in the human carcinoma cell line, hence the name. Ephrin-Eph interaction guides cells to reach their appropriate location in adult tissues. They also play an essential role in the immune system by helping in immune cell migration, adhesion, and activation. Based on their structure and function, Eph is divided into two classes — EphA and EphB.
2.6K
01:12Renewal of Skin Epidermal Stem Cells
2.9K
The skin is divided into epidermis, dermis, and hypodermis, the skin's outermost, middle, and inner layers. The human epidermal layer regularly undergoes renewal, where old, dead cells are replaced by new cells. Epidermal stem cells or EpiSCs divide and differentiate to restore the lost cells. For the renewal process, some EpiSCs continuously self-renew. In contrast, few others differentiate into transit-amplifying cells, which later form prickle or spinous cells, followed by granular...
2.9K
01:31Regulation of the Unfolded Protein Response
2.9K
Inositol-requiring kinase one or IRE1 is the most conserved eukaryotic unfolded protein response (UPR) receptor. It is a type I transmembrane protein kinase receptor with a distinctive site-specific RNase activity. As the binding mechanics of the misfolded proteins with the N-terminal domain of IRE-1 are unclear, three binding models — direct, indirect, and allosteric -- are proposed for receptor activation. Nevertheless, it is known that once a misfolded protein associates with IRE1, it...
2.9K
01:12Role Of Notch Signalling In Intestinal Stem Cell Renewal
2.4K
Notch signaling was first discovered in Drosophila melanogaster, where it is involved in cell lineage differentiation. Notch signaling regulates the maintenance and differentiation of intestinal stem cells or ISCs by controlling the expression of atonal homolog 1 or Atoh1. Atoh1 directs cells to differentiate into secretory cells.
Direct cell-to-cell contact is needed for the activation of Notch signaling. The signal is initiated when a notch ligand binds to a receptor on an adjacent cell, also...
Direct cell-to-cell contact is needed for the activation of Notch signaling. The signal is initiated when a notch ligand binds to a receptor on an adjacent cell, also...
2.4K
01:07MAPK Signaling Cascades
7.8K
Mitogen-activated protein kinase, or MAPK pathway, activates three sequential kinases to regulate cellular responses such as proliferation, differentiation, survival, and apoptosis. The canonical MAPK pathway starts with a mitogen or growth factor binding to an RTK. The activated RTKs stimulate Ras, which recruits Raf or MAP3 Kinase (MAPKKK), the first kinase of the MAPK signaling cascade. Raf further phosphorylates and activates MEK or MAP2 Kinases (MAPKK), which in turn phosphorylates MAP...
7.8K
01:25Cell Signaling in Plants
6.1K
Plant cells communicate to coordinate their cycle of growth, flowering and fruiting, and activities in roots, shoots, and leaves in response to the changing environmental conditions. Plant signaling is distinct from animal signaling. Plants primarily utilize enzyme-linked receptors, whereas the largest class of cell-surface receptors in animals are G-protein coupled receptors (GPCRs). Unlike animals, receptor tyrosine kinases are rare in plants. Instead, plants have a diverse class of...
6.1K