Mice lacking p63, a single gene that encodes a group of transcription factors that either contain (TA) or lack (Delta N) a transactivation domain, fail to develop stratified epithelia as well as epithelial appendages and limbs. Delta Np63 isoforms are predominantly expressed during late embryonic and postnatal epidermal development, however, the function of these proteins remains elusive. Using an epidermal-specific inducible knockdown mouse model, we demonstrate that Delta Np63 proteins are essential for maintaining basement membrane integrity and terminal differentiation of keratinocytes. Furthermore, we have identified two Delta Np63 alpha target genes that mediate these processes. We propose that Delta Np63 alpha initially induces expression of the extracellular matrix component Fras1, which is required for maintaining the integrity of the epidermal-dermal interface at the basement membrane. Subsequently, induction of I kappa B kinase-alpha by Delta Np63 alpha initiates epidermal terminal differentiation resulting in the formation of the spinous layer. Our data provide insights into the role of Delta Np63 alpha in epidermal morphogenesis and homeostasis, and may contribute to our understanding of the pathogenic mechanisms underlying disorders caused by p63 mutations.

Mice lacking p63, a single gene that encodes a group of transcription factors that either contain (TA) or lack (Delta N) a transactivation domain, fail to develop stratified epithelia as well as epithelial appendages and limbs. Delta Np63 isoforms are predominantly expressed during late embryonic and postnatal epidermal development, however, the function of these proteins remains elusive. Using an epidermal-specific inducible knockdown mouse model, we demonstrate that Delta Np63 proteins are essential for maintaining basement membrane integrity and terminal differentiation of keratinocytes. Furthermore, we have identified two Delta Np63 alpha target genes that mediate these processes. We propose that Delta Np63 alpha initially induces expression of the extracellular matrix component Fras1, which is required for maintaining the integrity of the epidermal-dermal interface at the basement membrane. Subsequently, induction of I kappa B kinase-alpha by Delta Np63 alpha initiates epidermal terminal differentiation resulting in the formation of the spinous layer. Our data provide insights into the role of Delta Np63 alpha in epidermal morphogenesis and homeostasis, and may contribute to our understanding of the pathogenic mechanisms underlying disorders caused by p63 mutations.

p63 induces key target genes required for epidermal morphogenesis

Costanzo A;
2007

Abstract

Mice lacking p63, a single gene that encodes a group of transcription factors that either contain (TA) or lack (Delta N) a transactivation domain, fail to develop stratified epithelia as well as epithelial appendages and limbs. Delta Np63 isoforms are predominantly expressed during late embryonic and postnatal epidermal development, however, the function of these proteins remains elusive. Using an epidermal-specific inducible knockdown mouse model, we demonstrate that Delta Np63 proteins are essential for maintaining basement membrane integrity and terminal differentiation of keratinocytes. Furthermore, we have identified two Delta Np63 alpha target genes that mediate these processes. We propose that Delta Np63 alpha initially induces expression of the extracellular matrix component Fras1, which is required for maintaining the integrity of the epidermal-dermal interface at the basement membrane. Subsequently, induction of I kappa B kinase-alpha by Delta Np63 alpha initiates epidermal terminal differentiation resulting in the formation of the spinous layer. Our data provide insights into the role of Delta Np63 alpha in epidermal morphogenesis and homeostasis, and may contribute to our understanding of the pathogenic mechanisms underlying disorders caused by p63 mutations.
Mice lacking p63, a single gene that encodes a group of transcription factors that either contain (TA) or lack (Delta N) a transactivation domain, fail to develop stratified epithelia as well as epithelial appendages and limbs. Delta Np63 isoforms are predominantly expressed during late embryonic and postnatal epidermal development, however, the function of these proteins remains elusive. Using an epidermal-specific inducible knockdown mouse model, we demonstrate that Delta Np63 proteins are essential for maintaining basement membrane integrity and terminal differentiation of keratinocytes. Furthermore, we have identified two Delta Np63 alpha target genes that mediate these processes. We propose that Delta Np63 alpha initially induces expression of the extracellular matrix component Fras1, which is required for maintaining the integrity of the epidermal-dermal interface at the basement membrane. Subsequently, induction of I kappa B kinase-alpha by Delta Np63 alpha initiates epidermal terminal differentiation resulting in the formation of the spinous layer. Our data provide insights into the role of Delta Np63 alpha in epidermal morphogenesis and homeostasis, and may contribute to our understanding of the pathogenic mechanisms underlying disorders caused by p63 mutations.
I kappa B kinase alpha; protein Fras1; protein p63; scleroprotein; article; basement membrane; cell differentiation; controlled study; enzyme induction; epidermis; extracellular matrix; gene function; gene induction; homeostasis; keratinocyte; morphogenesis; mouse; newborn; nonhuman; priority journal; protein expression; protein function; Animals; Blotting; Western; Cell Differentiation; Cell Line; DNA Primers; Epidermis; Gene Expression Regulation; Developmental; In Situ Nick-End Labeling; Keratinocytes; Mice; Transgenic; Microscopy; Fluorescence; Morphogenesis; Phosphoproteins; Potoroidae; Reverse Transcriptase Polymerase Chain Reaction; Trans-Activators; Wound Healing; Mus
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11699/6290
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