The Grainyhead-like epithelial transactivator Get-1/Grhl3 regulates epidermal terminal differentiation and interacts functionally with LMO4

Abstract

Defective permeability barrier is an important feature of many skin diseases and causes mortality in premature infants. To investigate the control of barrier formation, we characterized the epidermally expressed Grainyhead-like epithelial transactivator (Get-1)/Grhl3, a conserved mammalian homologue of Grainyhead, which plays important roles in cuticle development in Drosophila. Get-1 interacts with the LIM-only protein LMO4, which is co-expressed in the developing mammalian epidermis. The epidermis of Get-1(-/-) mice showed a severe barrier function defect associated with impaired differentiation of the epidermis, including defects of the stratum corneum, extracellular lipid composition and cell adhesion in the granular layer. The Get-1 mutation affects multiple genes linked to terminal differentiation and barrier function, including most genes of the epidermal differentiation complex. Get-1 therefore directly or indirectly regulates a broad array of epidermal differentiation genes encoding structural proteins, lipid metabolizing enzymes and cell adhesion molecules. Although deletion of the LMO4 gene had no overt consequences for epidermal development, the epidermal terminal differentiation defect in mice deleted for both Get-1 and LMO4 is much more severe than in Get-1(-/-) mice with striking impairment of stratum corneum formation. These findings indicate that the Get-1 and LMO4 genes interact functionally to regulate epidermal terminal differentiation.

Receptor-interacting Protein Kinase 4 and Interferon Regulatory Factor 6 Function as a Signaling Axis to Regulate Keratinocyte Differentiation

“…2, E and F). GRHL3, OVOL1, and mitotic arrestdeficient 1 (MAD1), which themselves are important transcriptional regulators of keratinocyte differentiation (37)(38)(39)(40)(41)(42), were also up-regulated in PMA-treated cells (Fig. 2, G-I).…”

Suppression of progenitor differentiation requires the long noncoding RNA ANCR

“…ANCR depletion disrupted normal expression of 388 annotated genes ( Fig. 3B; Supplemental Table S4), including CEBPA, GRHL3, and HOPX, all three of which are transcription factors known to regulate epidermal differentiation (Yu et al 2006;Lopez et al 2009;Yang et al 2010). Gene ontology (GO) analysis of genes differentially expressed upon ANCR depletion produced GO terms strongly enriched for epidermis differentiation, cornification, and keratinization (Fig.…”

Two Isoforms of Sister-of-Mammalian Grainyhead Have Opposing Functions in Endothelial Cells and In Vivo

“…26 However, because migration of keratinocytes depends on proliferation, unlike migration of EC, a completely different set of target genes might be induced. In addition, mice do not express homologs of the human SOM1 and SOM3 proteins since the corresponding first coding exon does not exist in the mouse genome and, therefore, these experiments would not have identified isoform-specific targets.…”