Koster Maranke I, Dai Daisy, Marinari Barbara, Sano Yuji, Costanzo Antonio, Karin Michael, Roop Dennis R
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA.
Proc Natl Acad Sci U S A. 2007 Feb 27;104(9):3255-60. doi: 10.1073/pnas.0611376104. Epub 2007 Feb 20.
Mice lacking p63, a single gene that encodes a group of transcription factors that either contain (TA) or lack (DeltaN) a transactivation domain, fail to develop stratified epithelia as well as epithelial appendages and limbs. DeltaNp63 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 DeltaNp63 proteins are essential for maintaining basement membrane integrity and terminal differentiation of keratinocytes. Furthermore, we have identified two DeltaNp63alpha target genes that mediate these processes. We propose that DeltaNp63alpha 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 IkappaB kinase-alpha by DeltaNp63alpha initiates epidermal terminal differentiation resulting in the formation of the spinous layer. Our data provide insights into the role of DeltaNp63alpha in epidermal morphogenesis and homeostasis, and may contribute to our understanding of the pathogenic mechanisms underlying disorders caused by p63 mutations.
缺乏p63基因的小鼠无法发育出分层上皮、上皮附属器和四肢。p63是一个单一基因，编码一组转录因子，这些转录因子要么含有（TA）要么缺乏（DeltaN）反式激活结构域。DeltaNp63亚型主要在胚胎后期和出生后表皮发育过程中表达，然而，这些蛋白质的功能仍然不清楚。利用表皮特异性诱导敲低小鼠模型，我们证明DeltaNp63蛋白对于维持基底膜完整性和角质形成细胞的终末分化至关重要。此外，我们鉴定出两个介导这些过程的DeltaNp63α靶基因。我们提出，DeltaNp63α最初诱导细胞外基质成分Fras1的表达，而Fras1是维持基底膜处表皮-真皮界面完整性所必需的。随后，DeltaNp63α诱导IkappaB激酶α的表达，启动表皮终末分化，导致棘层形成。我们的数据为DeltaNp63α在表皮形态发生和稳态中的作用提供了见解，并可能有助于我们理解由p63突变引起的疾病的致病机制。
