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We found a decrease in zig-zag hairs, whereas all the other hair types awl , auchene , and guard were increased in transgenic mice compared with nontransgenic mice Table 1. These alterations prompted us to analyze possible hair cycle defects; however, this study had to be limited to those mice that allowed the establishment of transgenic lines, namely L60 and L84, expressing myrAkt, and LA expressing wtAkt.

By 28—30 d after birth the time at which the first postnatal hair anagen is evident we observed that HFs in control Figure 2 E , L60 not shown , and LA Figure 2 F displayed clear anagen features. On the contrary, the HFs of L84 mice showed clear signs of outer root sheet hyperplasia and remained in telogen Figure 2 G , thus demonstrating that an increase in Akt activity above a certain level produces hair cycle defects. Subsequent analysis of multiple skin sections of different transgenic mice at different time points after birth indicated a loss of synchrony in the first postnatal hair cycle in the L84 mice Supplementary Figure 1.

Figure 2. Hair phenotype of myrAkt transgenic mice. A Example of alopecia in L60 mice affecting the snout and some patches of dorsal skin. Note the progressive degeneration. Note the absence of true anagen in L84 transgenic mice. H Representative histology of transgenic L84 skin by pnd Not the enlarged anagen HF structures denoted by arrows. Table 1.

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Hair type distribution. Another characteristic displayed by L84 transgenic mice and some founders were long and fragile nails Figure 3 A. Figure 3. Nail phenotype of myrAkt transgenic mice. A Example of nail overgrowth in founder Also the fragility of nails is depicted inset.

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Similar observations were obtained in L84 mice. With respect to teeth, most of L84 transgenic mice and some founders showed overgrowth and thinning of the incisors Figure 4 A , which in a few cases was also accompanied by the development of supernumerary teeth located in the palate arrow in Figure 4 B.

Additionally, in most cases the second or third molar primarily in the lower jaw, was missing arrow in Figure 4 C.

Figure 4. Tooth phenotype of myrAkt transgenic mice. Representative examples of transgenic mice showing overgrowth and fragility of the incisors A , supernumerary teeth located in the palate B , and lack of the second molar in the lower jaw C. We also characterized alterations in other ectodermal-derived structures. These are a special kind of sebaceous glands at the rim of the eyelids that have no association with adjacent hair follicles and produce a lipid secretion that forms a component of the tear film. Collectively, these data demonstrate that the expression of constitutively active Akt in the basal layer of stratified epithelia leads to altered development of multiple ectodermally derived organs in a dose-dependent manner.

Figure 5. Ectodermal gland phenotype of myrAkt transgenic mice. Note the hyperplasia of the meibomian, dysplasia of the salivary and hypoplasia of the sweat glands in transgenic mice. The development of ectodermal organs is controlled by multiple pathways involving numerous genes.

Most of these pathways modulate the process of hair cycling. The ectodermal and hair cycle defects observed in the transgenic mice suggested that increased and deregulated Akt activity leads to altered expression of genes involved in these developmental pathways. To gain a deeper insight into this aspect, we performed global expression profiling of paired RNA samples from whole skin extracts of transgenic L60, L84, and LA and nontransgenic mice at 30 d after birth.

The LA mice did not display the ectodermal alterations observed in L84, and in L60 mice only sporadic alopecia was detected in the snout, face, and back skin; none of these transgenic lines displayed hair cycle defects Figure 2 F; see also Supplementary Figure 1. Consequently, the microarray data were first processed to find specific clusters that included genes associated with the modest changes observed in L60 and the more dramatic alterations observed in L84 Figure 6 , A and B; clusters 1 and 2, down- and up-regulated, respectively.

Subsequently, we also searched for genes only deregulated in L84 compared with LA, controls, and L60 Figure 6 , A and B; clusters 3 and 4, down- and up-regulated, respectively. It is worth mentioning that, from the total genes identified, the largest number of changes correspond to those showing alterations only in L84 skin clusters 3 and 4 , which includes genes see Supplementary Tables 1—4 for the complete list of identified genes.

Figure 6. Summary of microarray data and Foxo3a expression. A Heatmap showing the relative expression of different genes selected for the analysis. C Summary of pathway integration of microarray analyses using Pathway Architect software Stratagene. Note the decreased staining and the reduced number of positive nuclei denoted by arrows in L To identify possible functional alterations in the different skin samples, we analyzed the biological functions of the genes mentioned above using DAVID software Dennis et al.

Utilizing the Entrez gene database, we narrowed the dataset to those genes that were involved in skin or ectodermal morphogenesis Table 3.

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Overall, these data indicate that deregulated Akt activity results in gene expression changes that can modulate epithelial development. Table 2. Functional annotation GOBP of genes selected from microarray analyses. Table 3.

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Representative genes involved in ectoderm development found in clusters. Bold face indicated genes that are involved in BMP signaling. Microarray data were further analyzed using Pathway Architect Stratagene to identify and characterize possible signaling pathways affected by specific alterations in gene expression. This analysis revealed that the global expression changes modify BMP4 signaling. In this regard, not only was the Bmp4 gene specifically down-regulated, but also negative regulators of BMP signaling such as Egf Nonaka et al. In addition, several genes found in these clusters are involved in BMP signaling Figure 6 C and highlighted in bold in Table 3 either as integral pathway effectors or as downstream targets Figure 6 C , thus suggesting that this developmental pathway is altered by myrAkt expression.

The forkhead transcription factor family has been widely described as a target of Akt Burgering and Kops, Direct phosphorylation of these factors by Akt results in their cytoplasmic retention and inactivation, inhibiting the expression of forkhead transcription factor-regulated genes Burgering and Kops, We thus studied whether the expression and localization of Foxo3a, a representative member of this family, is affected in the epidermis of the different transgenic mice by postnatal day pnd In control, nontransgenic mice Figure 6 D , we observed a positive staining throughout the epithelium, and a number of positive nuclei were detected in the hair follicle and the basal layer of the interfollicular epidermis denoted by arrows in Figure 6 D.

A similar staining pattern was observed in L60 Figure 6 E and LA Figure 6 F transgenic mice epidermis, although a minor decrease in the interfollicular epidermal positive nuclei was observed in L60 samples. On the contrary, in L84 skin Figure 6 G , the overall staining was decreased and very few positive nuclei were observed denoted by arrows in Figure 6 G. Therefore, in agreement with our previous data Segrelles et al. This might help to explain, at least in part, some of the changes observed in microarray analyses.

BMP signaling is thought to perform multiple functions in the regulation of skin appendage morphogenesis and the postnatal growth of HFs Botchkarev, Therefore, to further confirm the possible alterations in BMP signaling, we carried out a detailed histology analysis of several components of this pathway. With respect to myrAkt transgenic mice, we observed altered distribution and localization of both morphogens Figure 7 , C and D, respectively , because scattered expression was observed in only a few cells.

Western blot analysis of whole skin extracts Figure 7 E confirmed the dramatic decrease in the level of BMP4. Figure 7. Altered BMP expression and localization in hair follicles of myrAkt transgenic mice. E Western blot of whole skin extracts probed for the expression of the indicated proteins. By full anagen pnd 28 , phospho-Smad staining was present in cells of the medulla, cortex, and cuticle of the hair shaft in nontransgenic and LA mice Figure 8 m A and B, respectively. These results are similar to previous reports Kobielak et al. In contrast, phospho-Smad staining in myrAkt transgenic mice was faint, and only a few cells expressed very low amounts at the tip of the hair Figure 8 C.

The apparent decrease in phospho-Smad was confirmed by Western blot of whole skin extracts Figure 7 E. Figure 8. Altered BMP signaling in hair follicles of myrAkt transgenic mice. This protein is an ectoderm-specific direct transcriptional target of BMP signaling Bakkers et al. There are several lines of evidence indicating that BMP signaling may influence the behavior of epidermal stem cells Sharov et al. Because the K5 promoter is also active in these cells, we have thus studied possible alterations in the stem cell population in the skin of L84 transgenic mice.

Initially we determined the expression of two putative epidermal stem cell markers, K15 and CD34 Liu et al. We next determined whether the epidermal stem cell compartment was affected by myrAkt expression using a label-retaining LR technique Cotsarelis et al. Finally, we also performed a colony-forming efficiency experiment using adult epidermis as the source of primary keratinocytes.

Five days after plating, multiple abortive colonies were observed in cultures from control mice Figure 9 F , and very few rendered productive colonies after long-term culture Figure 9 G. Collectively, these data indicate that constitutively active Akt expression results in an expansion of the stem cell population. Figure 9. Alterations in L84 epidermal stem cell population. Note the apparent increase in the double positive cells in L84 hair follicle. Brackets denote bulge region b. Sebaceous glands are denoted by sg. Arrowheads denote BrdU-positive follicle cells.

C Summary of three independent LRC experiments showing the percentage of hair follicles containing positive cells as previously reported Ruiz et al. G Representative example of the colony-forming efficiency of primary keratinocytes derived from control and L84 adult 8 wk mice 3 wk after plating. In the current study we present data that strongly support the hypothesis that increased and deregulated Akt activity, triggered by myrAkt expression, provokes dramatic alterations in ectodermal organ development. Collectively, these findings support the conclusions that Akt is an important mediator of epithelial homeostasis.

The fact that increased wild-type Akt expression as in wtAkt mice , which requires upstream control elements to become fully activated Segrelles et al. Our results are in agreement with the reported alterations found in different mouse models of Akt deficiency Di-Poi et al.

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  • Of note, data obtained from double Akt KO mice, besides arguing for partially overlapping functions of Akt isoforms in vivo, also revealed that some functions of Akt are only discernible when total Akt levels are below a critical threshold in specific cell types and tissues Dummler et al. Further evaluation of ectodermal derived organs in compound Akt KO mice may reveal additional roles. The Akt signaling pathway has been widely studied in the context of carcinogenesis Manning and Cantley, and is associated with increased cell proliferation and survival.

    This would indicate that the observed development defects due to increased Akt activity can be delineated from proliferative or antiapoptotic effects. We have taken this aspect as a starting hypothesis for the analysis of the microarray data. Indeed, the consideration of genes that do not display altered expression in LA epidermis certainly restricts the analyses. The list of genes found is relatively small and includes multiple genes previously associated with ectoderm or skin development. Furthermore, in unconstrained analysis of possible pathways involved, we detected the BMP-dependent pathway, indicating that this may be a major mediator in the skin phenotypic alterations found in myrAkt mice.

    The possibility that this pathway is also a target mediating other ectodermal alterations seems plausible but undoubtedly will require further investigations. It is widely recognized that BMP signaling is required for proper development of several ectodermal structures reviewed in Jernvall and Thesleff, ; Botchkarev, Of note, cre -mediated mutation of the BMPR1A gene causes altered tooth morphogenesis, defective postnatal development of HFs, and abnormal nail growth Andl et al.

    In agreement, we also observed the development of epithelial tumors in Akt transgenic mice that in many cases were associated with hair follicle structures Segrelles et al. Although epidermal-specific deletion of the Bmpr1a gene or Noggin overexpression caused severe alterations in the expression of several genes associated with development and cell cycle Kobielak et al. This difference may be due to the fact that ablation of BmprIa or Noggin overexpression completely abrogates BMP signaling, whereas our data support a possible deregulation together with decreased signaling rather than complete inhibition.

    As an alternative explanation, searching for genes displaying a selected pattern of expression may obscure or lead to an incomplete analysis of the data. Indeed, as mentioned above, the genes found through the unrestricted analysis of the microarray data also included most of the genes reportedly altered in BmprIa conditional KO and Noggin transgenic mice. Nevertheless this group of genes was also altered in wtAkt transgenic mice that do not display ectodermal defects. The present data complement these observations and show through microarray and histology analyses that deregulated Akt activity affects BMP signaling and, as an overall consequence, the BMP pathway is at least partially inhibited.

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    The molecular bases of this alteration in Bmp4 expression are not known at present; however, among the multiple regulators of Bmp4 gene expression there are several putative candidates that can be modulated by Akt activity. In this regard, p65 RelA , which can be activated by Akt Madrid et al. In this regard, the altered expression and distribution of Foxo3a observed in L84 epidermis might explain the reduced expression of Bmp4.

    Further studies will help to clarify the functional impact of Akt activity on Bmp4 expression. Many of the alterations observed in the ectodermal organs of myrAkt mice were similar to the defects present in mice resembling human ectodermal dysplasia syndromes Thesleff, The possibility that Akt may be involved in these disorders is very intriguing and would certainly merit further investigations. The finding that expression level of this protein was not altered in myrAkt transgenic mice relative to nontransgenic mice indicates that other targets of Akt kinase may be responsible for the observed phenotype.

    In this regard, the previously reported cross talk between the glucocorticoid receptor and Akt Leis et al. In the current study we observed that deregulated Akt activity results in altered homeostasis of adult epidermal stem cells.

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    On the other hand, the alterations in stem cells observed in the epidermis of myrAkt mice also agree with the reported modulation of these cells by BMP signaling in epidermis and other tissues Kobielak et al. It has been reported that this suprabasal cell population is derived from that which maintains basal lamina contact and arises only after the start of the first postnatal hair cycle Blanpain et al.

    Our data implicate that Akt may affect the transition between these two cell populations and would suggest that Akt may control the cross talk between stem cells and the niche microenvironment. Collectively, we present evidence that ectodermal organ development is dependent on accurate Akt signaling and that deregulation of this activity results in altered development of these organs, which in the case of skin proceeds through altered BMP signaling and affects epidermal stem cell population.

    E on October 24, Molecular Biology of the Cell Vol. This is the final version - click for previous version. Add to favorites Download Citations Track Citations. Abstract Aberrant activation of the Akt pathway has been implicated in several human pathologies including cancer. Representative genes involved in ectoderm development found in clusters Cluster Gene symbol Fold change in L84 1 Axin2 Epithelial Bmpr1a regulates differentiation and proliferation in postnatal hair follicles and is essential for tooth development.

    Development , Zebrafish DeltaNp63 is a direct target of Bmp signaling and encodes a transcriptional repressor blocking neural specification in the ventral ectoderm. Cell 2 , Delta Np63 alpha expression is regulated by the phosphoinositide 3-kinase pathway. Chem , Oncogene 24 , Activation of AKT kinases in cancer: implications for therapeutic targeting.

    Cancer Res 94 , Epidermal stem cells of the skin. Annu Rev.

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    Cell Dev. Biol 22 , Self-renewal, multipotency, and the existence of two cell populations within an epithelial stem cell niche. Cell , Severe follicular hyperplasia and spontaneous papilloma formation in transgenic mice expressing the neu oncogene under the control of the bovine keratin 5 promoter. Carcinog 21 , A comparison of normalization methods for high density oligonucleotide array data based on variance and bias.

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