Apoptosis, differentiation, and proliferation are cellular responses which play a pivotal role in wound healing. During this process PPARbeta translates inflammatory signals into prompt keratinocyte responses. We show herein that PPARbeta modulates Akt1 activation via transcriptional upregulation of ILK and PDK1, revealing a mechanism for the control of Akt1 signaling. The resulting higher Akt1 activity leads to increased keratinocyte survival following growth factor deprivation or anoikis. PPARbeta also potentiates NF-kappaB activity and MMP-9 production, which can regulate keratinocyte migration. Together, these results provide a molecular mechanism by which PPARbeta protects keratinocytes against apoptosis and may contribute to the process of skin wound closure.

Hox genes are central to the specification of structures along the anterior-posterior body axis 1,2 , and modifications in their expression have paralleled the emergence of diversity in vertebrate body plans 3,4 . Here we describe the genomic organization of Hox clusters in different reptiles and show that squamates have accumulated unusually large numbers of transposable elements at these loci 5 , reflecting extensive genomic rearrangements of coding and non-coding regulatory regions. Comparative expression analyses between two species showing different axial skeletons, the corn snake and the whiptail lizard, revealed major alterations in Hox13 and Hox10 expression features during snake somitogenesis, in line with the expansion of both caudal and thoracic regions. Variations in both protein sequences and regulatory modalities of posterior Hox genes suggest how this genetic system has dealt with its intrinsic collinear constraint to accompany the substantial morphological radiation observed in this group.In many animal species, Hox genes are clustered, and their expression domains, in both time and space, reflect their respective genomic order 1 . Although this genetic system has been used as a paradigm in the study of the evolution of body plans 6 , recent studies have highlighted an unexpected diversity in Hox gene number, genomic organization and expression patterns 7,8 . In tetrapods, these genes are classified into 13 groups of paralogy and are tightly clustered at four loci: HoxA to HoxD. A clear correspondence between particular Hox groups and defined morphological boundaries along the anteroposterior axis has been documented, either by comparing expression profiles between various vertebrates or by genetic experiments in the mouse 1,3,4,9 .Vertebrate species have highly variable number of vertebrae, ranging from fewer than ten to several hundreds 10-12 , a parameter that is probably dependent on the speed of the segmentation clock relative to axial growth, as proposed for snakes 13 . Within reptiles, squamates (that is, lizards and snakes) have a large realm of morphologies, suggesting that Hox genes were modified, either in their structure or in their regulation. Previous expression analyses in snakes showed an expansion of anterior Hox gene expression along the body axis, in parallel with body plan elongation 9 , and revealed that collinearity was fully respected 14 . However, these studies involved selected genes, in the absence of genomic information. Here we describe how structural and regulatory adaptations in this gene family may have accompanied the transition towards such a body plan and suggest that the unexpected invasion of all Squamata Hox clusters by transposons might have facilitated such adaptations.We characterized the genomic organization of posterior Hox loci in the corn snake (Pantherophis guttatus) and other reptiles, including the turtle, tuatara and several lizards, with a particular focus on repeated elements that are generally excluded from these loci in tetrapods but are abundan...

Akt/protein kinase B (PKB) plays a critical role in the regulation of metabolism, transcription, cell migration, cell cycle progression, and cell survival. The existence of viable knockout mice for each of the three isoforms suggests functional redundancy. We generated mice with combined mutant alleles of Akt1 and Akt3 to study their effects on mouse development. Here we show that Akt1 ؊/؊ Akt3 ؉/؊ mice display multiple defects in the thymus, heart, and skin and die within several days after birth, while Akt1 ؉/؊ Akt3 ؊/؊ mice survive normally. Double knockout (Akt1 ؊/؊ Akt3 ؊/؊ ) causes embryonic lethality at around embryonic days 11 and 12, with more severe developmental defects in the cardiovascular and nervous systems. Increased apoptosis was found in the developing brain of double mutant embryos. These data indicate that the Akt1 gene is more essential than Akt3 for embryonic development and survival but that both are required for embryo development. Our results indicate isoform-specific and dosage-dependent effects of Akt on animal survival and development.In mammals, Akt1, Akt2, and Akt3 (also called protein kinase B␣ [PKB␣], PKB␤, and PKB␥) proteins have similar domain structures and can be activated by numerous growth factors in a phosphatidylinositol 3-kinase-dependent manner (1,3,4,15,23). Once activated, Akt phosphorylates and controls the activities of a diverse group of substrates involved in many cellular and physiological processes, such as cell survival, cell cycle progression, cell growth, metabolism, and angiogenesis (3,10,17,23).Although many proteins have been identified as Akt substrates, the challenge that remains is to show that they actually have an important impact on physiological processes in organisms. Recently, targeted deletion of specific isoforms of Akt in mice has proved to be a powerful tool for elucidating the physiological roles of Akt proteins (5,7,8,13,16,25,27,28). Characterization of such knockout mice has yielded intriguing and surprising results. We and others found that ϳ40% of Akt1 knockout mice die at a neonatal stage with growth retardation, but the other ϳ60% of Akt1 knockout mice survive apparently normally. This suggests that the other two remaining Akt isoforms can, in part, compensate for the loss of one Akt. Knockout of each single isoform gives rise to a distinct phenotype. In general, Akt1 null mice are growth retarded, which may result from placental insufficiency, while Akt2-deficient mice suffer from a type 2 diabetes-like syndrome and Akt3 null mice show impaired brain development (5,7,8,13,16,25,27,28). These observations indicate that the three Akt isoforms have different nonredundant physiological functions. The relatively normal development and distinct physiological functions exhibited by single knockouts may be explained by differences in the tissue distribution and expression levels of these isoforms. We found that Akt1 is the major isoform in placenta and that placenta lacking this protein cannot form a proper vascular labyrinth; this may restric...

Researchers show that scales, feathers, and hairs of reptiles, birds, and mammals evolved from the scales of their common reptilian ancestor.