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Jürgen Schweizer

Publications and source records attributed to Jürgen Schweizer.

At least 19 recordsLinked to original sources
PubMed2006

K25 (K25irs1), K26 (K25irs2), K27 (K25irs3), and K28 (K25irs4) represent the type I inner root sheath keratins of the human hair follicle.

The recent elucidation of the human type I keratin gene domain allowed the completion of the so far only partially characterized subcluster of type I keratin genes, KRT25-KRT28 (formerly KRT25A-KRT25D), representing the counterparts of the type II inner root sheath (IRS) keratin genes, KRT71-KRT74 (encoding proteins K71-K74, formerly K6irs1-K6irs4). Here, we describe the expression patterns of the type I IRS keratin proteins K25-K28 (formerly K25irs1-K25irs4) and their mRNAs. We found that K25 (K25irs1), K27 (K25irs3), and K28 (K25irs4) occur in the Henle layer, the Huxley layer, and in the IRS cuticle. Their expression extends from the bulb region up to the points of terminal differentiation of the three layers. In contrast, K26 (K25irs2) is restricted to the upper IRS cuticle. Apart from the three IRS layers, K25 (K25irs1), K27 (K25irs3), and K28 (K25irs4) are also present in the hair medulla. Based on previous, although controversial claims of the occurrence in the IRS of various "classical" epithelial keratins, we undertook a systematic study using antibodies against the presently described human epithelial and hair keratins and show that the type I keratins K25-K28 (K25irs1-K25irs4) and the type II keratins K71-K74 (K6irs1-K6irs4) represent the IRS keratins of the human hair follicle.

Antibodies↗
PubMed2006

New consensus nomenclature for mammalian keratins.

Keratins are intermediate filament-forming proteins that provide mechanical support and fulfill a variety of additional functions in epithelial cells. In 1982, a nomenclature was devised to name the keratin proteins that were known at that point. The systematic sequencing of the human genome in recent years uncovered the existence of several novel keratin genes and their encoded proteins. Their naming could not be adequately handled in the context of the original system. We propose a new consensus nomenclature for keratin genes and proteins that relies upon and extends the 1982 system and adheres to the guidelines issued by the Human and Mouse Genome Nomenclature Committees. This revised nomenclature accommodates functional genes and pseudogenes, and although designed specifically for the full complement of human keratins, it offers the flexibility needed to incorporate additional keratins from other mammalian species.

Animals↗
PubMed2006

Human hair keratin-associated proteins: sequence regularities and structural implications.

In this paper, we undertake a sequence analysis of the human keratin-associated proteins (KAP). This analysis has revealed two fundamental pentapeptide quasi-repeats (A and B) of the form C-C-X-P-X and C-C-X-S/T-S/T, respectively. The A repeats are also commonly found in two subforms A1 and A2, -C-C-Q-P-X and C-C-R-P-X, respectively-similar to those found in sheep wool 30-40 years previously. Some high-sulphur and ultra-high sulphur proteins contain predominantly A repeats or B repeats but not regular combinations of them, whereas others are characterised by a contiguous pair of pentapeptide repeats that largely (though imperfectly) alternate to generate decapeptide motifs of the form AB, A1B or A2B. The A and B repeats sometimes occur in complex runs and can generate both 19- and 20-residue repeats of the form BABB' or BA1AA, respectively, where the prime indicates a motif truncated by one residue. Likewise, a 42-residue repeat with BA1BXAAAB (40 residues) separated by a di-serine (two residues) has been observed in an ultra-high sulphur protein from cuticle. To understand the possible conformations adopted by the A and B motifs, a search was initiated of the PDB structural database for a number of overlapping pentapeptide repeats. The total number of matches was 658 and these were found in 451 different proteins. From representative and unique structures the means and standard deviations were calculated for the Phi(i) and Psi(i) angles for the C-C-X-P-X and the C-C-X-S/T-S/T motifs. Molecular modelling has been employed to represent the "average" structure found from crystallographic and nmr data determined for each motif in other proteins. The conformation of consecutive A repeats with proline residues in the cis state is akin to a string of disulphide bond-stabilised pentapeptide knots between which there is relative freedom of rotation about the single bonds that link them. For B pentapeptides, however, the likelihood that a similar disulphide bond is formed appears much lower. This may give additional conformational flexibility to the chain and hence allow the A pentapeptides greater opportunity to interact appropriately with the IF via disulphide bonds, ionic interactions and/or hydrogen bonding.

Amino Acid Sequence↗
PubMed2006

Human hair keratin-associated proteins (KAPs).

Elucidation of the genes encoding structural proteins of the human hair follicle has advanced rapidly during the last decade, complementing nearly three previous decades of research on this subject in other species. Primary among these advances was both the characterization of human hair keratins, as well as the hair keratin associated proteins (KAPs). This review describes the currently known human KAP families, their genomic organization, and their characteristics of expression. Furthermore, this report delves into further aspects, such as polymorphic variations in human KAP genes, the role that KAP proteins might play in hereditary hair diseases, as well as their modulation in several different transgenic mouse models displaying hair abnormalities.

Amino Acid Sequence↗
PubMed2006

Expression patterns of hair and epithelial keratins and transcription factors HOXC13, LEF1, and beta-catenin in a malignant pilomatricoma: a histological and immunohistochemical study.

BACKGROUND: We have previously shown that benign pilomatricomas not only maintain the sequential expression of the hair matrix and precortex keratins hHa5 and hHa1 of normal hair follicles in their transitional cell compartment, but also preserve the association of hHa5 expression with that of its regulatory homeoprotein HOXC13 in the lower transitional cell compartment. In contrast, hHa1 expression in the upper transitional cell compartment is uncoupled from the nuclear co-expression of the LEF1/beta-catenin complex seen in normal hair follicles (Cribier et al., J Invest Dermatol 2004; 122: 1078). METHODS: Formalin-fixed paraffin sections of the tumor were examined using a panel of mono- and polyclonal hair and epithelial keratin antibodies as well as antibodies against HOXC13, LEF1, and beta-catenin. RESULTS: Morphologically, the malignant pilomatricoma investigated here clearly deviated from the described major tumor type by a large number of differently sized parakeratotic squamoid whorls emerging within the mass of basaloid cells and surrounded by cells remembering transitional cells, but only rarely containing shadow cells and signs of calcification. We show that hHa5/HOXC13 co-expression was maintained in transitional cell areas, in which hHa1 expression was much stronger than in benign pilomatricomas, but again uncoupled from concomitant nuclear LEF1/beta-catenin expression. Surprisingly, however, and in clear contrast to benign pilomatricomas, these transitional cells co-expressed the epithelial keratins K5, K14, and K17, with the latter being as strongly expressed as hHa1, both also staining the entire inner mass of the parakeratotic whorls. CONCLUSIONS: Although the malignant pilomatricoma investigated here was distinctive in that it contained a multitude of parakeratinizing whorls and no signs of calcification, it shared both hHa5/HOXC13 co-expression and disrupted hHa1/beta-catenin-LEF1 expression in its transitional cell compartment around the whorls with benign pilomatricomas. However, in clear contrast to the latter, transitional cells of the malignant tumor also strongly expressed the epithelial keratins K5, K14, and K17. We speculate that the observed dominance of the epithelial differentiation pathway over the competing conventional shadow cell differentiation pathway may prevent massive calcification of the tumor.

Aged, 80 and over↗
PubMed2005

The HOXC13-controlled expression of early hair keratin genes in the human hair follicle does not involve TALE proteins MEIS and PREP as cofactors.

We previously showed that the homeodomain protein HOXC13 is involved in the expression control of the early human hair keratin genes hHa5 and hHa2, which contain specific HOXC13 binding sites in their proximal promoters. Hox specificity is generally thought to be enhanced by the interaction with members of the TALE superclass of homeodomain proteins Pbx, Meis, and Prep. Using reverse transcription PCR with total human hair follicle RNA, we demonstrated transcripts of the major TALE proteins PBX1-4, MEIS1, 2 and PREP1, 2 in the human hair follicle. In view of the presence of MEIS/PREP responsive elements in close vicinity to the HOXC13 binding sites of the hHa5 and hHa2 promoters, we determined the expression sites of these TALE proteins in the human hair follicle. We found that MEIS1, MEIS2, PREP1 and PREP2 were differentially expressed in the three layers of the inner root sheath. In addition, MEIS2 and PREP1 exhibited expression in the mid-to upper hair cortex, with PREP1 being also expressed in the dermal papilla and the connective tissue sheath of the hair follicle. In virtually all cases, the expression of these TALE proteins was exclusively cytoplasmic. Considering that in contrast, HOXC13 is expressed in the nuclei of matrix, precortex and lower cuticle cells of the hair follicle, our data suggest that despite the presence of MEIS/PREP binding sites in the hHa5 and hHa2 promoters, the HOXC13-controlled activation of these genes in the hair follicle does not seem to involve these TALE proteins as cofactors.

Cell Nucleus↗
PubMed2005

Keratins of the human hair follicle.

Substantial progress has been made regarding the elucidation of differentiation processes of the human hair follicle. This review first describes the genomic organization of the human hair keratin gene family and the complex expression characteristics of hair keratins in the hair-forming compartment. Sections describe the role and fate of hair keratins in the diseased hair follicle, particularly hereditary disorders and hair follicle-derived tumors. Also included is a report on the actual state of knowledge concerning the regulation of hair keratin expression. In the second part of this review, essentially the same principles are applied to outline more recent and, thus, occasionally fewer data on specialized epithelial keratins expressed in various tissue constituents of the external sheaths and the companion layer of the follicle. A closing outlook highlights issues that need to be explored further to deepen our insight into the biology and genetics of the hair follicle.

Animals↗
PubMed2005

Characterization of new members of the human type II keratin gene family and a general evaluation of the keratin gene domain on chromosome 12q13.13.

The recent completion of a reference sequence of the human genome now allows a complete characterization of the type II keratin gene domain on chromosome 12q13.13. This, domain, approximately 780 kb in size, is present on nine bacterial artificial chromosome clones sequenced by the Human Genome Sequencing Project. The type II keratin domain contains 27 keratin genes and eight pseudogenes. Twenty-three of these genes and four pseudogenes have been previously reported. This study describes, in addition to the genomic sequencing of the K2p gene and the bioinformatic identification of four keratin pseudogenes, the characterization of cDNA corresponding to three previously undescribed keratin genes K1b, K6l, and Kb20, as well as cDNA sequences for the previously described keratin genes hHb2, hHb4, and K3. Northern analysis of the new keratins K1b, K6l, K5b, and Kb20 using mRNA of major organs as well as of specific epithelial subtypes shows singular expression of these keratins in skin, hair follicles and, for K5b and Kb20, in tongue, respectively. In addition, the obvious discrepancies between the current reference sequence of the human genome and the previously described gene/cDNA sequences for K6c, K6d, K6e, K6f, K6h are investigated, leading to the conclusion that K6c, K6d as well as K6e, K6f are probably polymorphic variants of K6a and K6h, respectively. All 26 human type II keratins found on this domain as well as K18, dtype 1 Keratin, are identified at the genomic and transcriptional level. This appears to be the total complement of functional type II keratins in humans.

Chromosomes, Human, Pair 12↗
PubMed2005

Characterization of a novel human type II epithelial keratin K1b, specifically expressed in eccrine sweat glands.

In this study, we show that a novel human type II epithelial keratin, K1b, is exclusively expressed in luminal duct cells of eccrine sweat glands. Taking this luminal K1b expression as a reference, we have used antibodies against a plethora of epithelial keratins to systematically investigate their expression in the secretory globule and the two-layered sweat duct, which was divided into the intraglandular, intradermal, and intraepidermal (acrosyringium) segments, the latter being further subdivided into the sweat duct ridge and upper intraepidermal duct. We show that (i) each of the eccrine sweat gland tissue compartments expresses their own keratin patterns, (ii) the peripheral and luminal duct layers exhibit a sequential keratin expression, with both representing self-renewing cell layers, (iii) the intradermal duct and the sweat duct ridge display hitherto unknown length variations, and (iv) out of all cell layers, the luminal cell layer is the most robust layer and expresses the highest number of keratins, these being concentrated at the apical side of the cells to form the cuticle. We provide evidence that the cellular and intercellular properties of the peripheral and the luminal layers reflect adaptations to different functions.

Amino Acid Sequence↗
PubMed2004

Krtap16, characterization of a new hair keratin-associated protein (KAP) gene complex on mouse chromosome 16 and evidence for regulation by Hoxc13.

Intermediate filament (IF) keratins and keratin-associated proteins (KAPs) are principal structural components of hair and encoded by members of multiple gene families. The severe hair growth defects observed upon aberrant expression of certain keratin and KAP genes in both mouse and man suggest that proper hair growth requires their spatio-temporally coordinated activation. An essential prerequisite for studying these cis-regulatory mechanisms is to define corresponding gene families, their genomic organization, and expression patterns. This work characterizes eight recently identified high glycine/tyrosine (HGT)-type KAP genes collectively designated Krtap16-n. These genes are shown to be integrated into a larger KAP gene domain on mouse chromosome 16 (MMU16) that is orthologous to a recently described HGT- and high sulfur (HS)-type KAP gene complex on human chromosome 21q22.11. All Krtap16 genes exhibit strong expression in a narrowly defined pattern restricted to the lower and middle cortical region of the hair shaft in both developing and cycling hair. During hair follicle regression (catagen), expression levels decrease until expression is no longer detectable in follicles at resting stage (telogen). Since isolation of the Krtap16 genes was based on their differential expression in transgenic mice overexpressing the Hoxc13 transcriptional regulator in hair, we examined whether bona fide Hoxc13 binding sites associated with these genes might be functionally relevant by performing electrophoretic mobility shift assays (EMSAs). The data provide evidence for sequence-specific interaction between Hoxc13 and Krtap16 genes, thus supporting the concept of a regulatory relationship between Hoxc13 and these KAP genes.

Amino Acid Motifs↗
PubMed2004

Hair keratin associated proteins: characterization of a second high sulfur KAP gene domain on human chromosome 21.

Analysis of the EBI/GeneBank database using nonhuman hair keratin associated protein (KAP) gene sequences as a query resulted in the identification of two human KAP gene domains on chromosome 21, one of which, located at 21q22.1, has recently been characterized. The second domain presented here, an approximately 90 kb domain on chromosome 21q23, harbored 16 KAP genes and two KAP pseudogenes. By comparison with known sheep and mouse KAP families, these genes could be assigned to two KAP families, KAP10 and KAP12, with the KAP10 family (12 members) being distinctly larger than the KAP12 family (four members). Systematic cDNA/3' rapid amplification of cDNA ends isolation studies using human scalp mRNA led to the identification of eight KAP10 and two KAP12 cDNA sequences. In situ hybridization analyses of human anagen hair follicles using specific 3'-noncoding sequences of the various KAP10/KAP12 genes revealed mRNA expression of nearly all KAP10 and KAP12 members exclusively in a narrow region of the middle portion of the hair fiber cuticle. Bioinformatic analyses of the promoter regions of the KAP10/KAP12 genes demonstrated several enhancer elements that were present in nearly all of the KAP genes. Primary among these were binding elements for the ETS, heat shock factor, AML, and HOX families of transcription factors.

Amino Acid Sequence↗
PubMed2004

An unusual Ala12Thr polymorphism in the 1A alpha-helical segment of the companion layer-specific keratin K6hf: evidence for a risk factor in the etiology of the common hair disorder pseudofolliculitis barbae.

Pseudofolliculitis barbae (PFB) is a common hair disorder characterized by a pustular foreign body inflammatory reaction that is induced by ingrown hairs of the facial and submental (barbea) regions after regular shaving. It occurs predominantly in black males, while it is rather rare and usually far less severe in Caucasian males. Black individuals have a higher propensity of developing PFB due to their genetic predisposition for curly hair which inherently possesses a much higher risk of growing back into the skin than straight or wavy hair. The PFB process is, however, not gender dependent nor restricted to the face, but can occur in any skin region once regular shaving, plucking, or other traumatic means of hair removal are instituted. Through a family study and a large-scale investigation of randomly sampled PFB-affected and -unaffected individuals, this study demonstrates that an unusual single-nucleotide polymorphism, which gives rise to a disruptive Ala12Thr substitution in the 1A alpha-helical segment of the companion layer-specific keratin K6hf of the hair follicle, is partially responsible for the phenotypic expression and represents an additional genetic risk factor for PFB.

Cells, Cultured↗
PubMed2004

On the regulation of hair keratin expression: lessons from studies in pilomatricomas.

Human hair follicles exhibit a complex pattern of sequential hair keratin expression in the hair matrix, cuticle, and cortex. In pilomatricomas, that is, benign skin tumors thought to arise from germinative matrix cells of the hair follicle and retaining morphological signs of cortical differentiation, this differential hair keratin pattern has been shown to be faithfully preserved in the lower and upper transitional cell compartments of the tumors. Here we show that also the co-expression of hair keratin hHa5 with its regulatory nuclear homeoprotein HOXC13 in matrix cells of the hair follicle is maintained in lower transitional cells of pilomatricomas. In contrast, the nuclear co-expression of LEF1 and beta-catenin, which in the hair follicle has been postulated to initiate cortex cell differentiation through the induction of hair keratin hHa1 expression (Merill et al, Genes Dev 15:1688-1705, 2001), is not preserved in upper transitional cells of pilomatricomas. Although these cells correctly express hHa1, they are completely devoid of LEF1 and nuclear LEF1/beta-catenin co-expression is shifted to a subpopulation of hair keratin-free basaloid cells of the tumors. These data imply that unlike the normal hair follicle, cortical differentiation in pilomatricomas is not under the control of the canonical Wnt signaling pathway.

Cytoskeletal Proteins↗
PubMed2004

The human type I keratin gene family: characterization of new hair follicle specific members and evaluation of the chromosome 17q21.2 gene domain.

In general concurrence with recent studies, bioinformatic analysis of the chromosome 17q21.2 DNA sequence found in the EBI/Genebank database shows the presence of 27 type I keratin genes and five keratin pseudogenes present on 8 contiguous Bacterial Artificial Chromosome (BAC) sequences. This constitutes the 970 kb type I keratin gene domain. Inserted into this domain is a 350 kb region harboring 32 previously characterized keratin-associated protein genes. Of the 27 keratin genes found in this region, six have not been characterized in detail. This study reports the isolation of cDNA sequences for these keratin genes, termed K25irs1-K25irs4, Ka35, and Ka36, as well as cDNA sequences for the previously reported hair keratins hHa3-I, hHa7, and hHa8. RT-PCR analysis of 14 epithelial tissues using primers for the six novel keratins, as well as for keratins 23 and 24, shows that the six novel keratins appear to be hair follicle associated. Previous expression data, coupled with evolutionary analysis studies point to K25irs1-K25irs4 probably being inner root sheath specific keratins. Ka35 and Ka36 are, based on their exon-intron structure and expression characteristics, hair keratins. In contrast, K23 and K24 appear to be epithelial keratins associated with simple/glandular or stratified, non-cornified epithelia, respectively. A literature analysis coupled with the data presented here confirms that all of the 27 keratin genes found on this domain have been characterized at the transcriptional level. Together with K18, a type I keratin gene found on the type II keratin domain, this seems to be the entire complement of functional type I keratins in humans.

Amino Acid Sequence↗
PubMed2003

K6irs1, K6irs2, K6irs3, and K6irs4 represent the inner-root-sheath-specific type II epithelial keratins of the human hair follicle.

In this study we report on the cloning of two novel human type II keratin cDNAs, K6irs3 and K6irs4, which were specifically expressed in the inner root sheath of the hair follicle. Together with the genes of two previously described type II inner root sheath keratins, K6irs1 and K6irs2, the K6irs3 and K6irs4 genes were subclustered in the type II keratin/hair keratin gene domain on chromosome 12q13. Evolutionary tree analysis using all known type II epithelial and hair keratins revealed that the K6irs1-4 formed a branch separate from the other epithelial and hair keratins. RNA in situ hybridization and indirect immunofluorescence studies of human hair follicles, which also included the K6irs2 keratin, demonstrated that both K6irs2 and K6irs3 were specifically expressed in the inner root sheath cuticle, but showed a different onset of expression in this compartment. Whereas the K6irs3 expression began in the lowermost bulb region, that of K6irs2 was delayed up to the height of the apex of the dermal papilla. In contrast, the K6irs4 keratin was specifically expressed in the Huxley layer. Moreover, K6irs4 was ideally suited to further investigate the occurrence of Flügelzellen, i.e., Huxley cells, characterized by horizontal cell extensions that pass through the Henle layer, abut upon the companion layer, and form desmosomal connections with the surrounding cells. Previously, we detected Flügelzellen only in the region along the differentiated Henle layer. Using the Huxley-cell-specific K6irs4 antiserum, we now demonstrate this cell type to be clearly apposed to the entire Henle layer. We provide evidence that Flügelzellen penetrate the Henle layer actively and may play a role in conferring plasticity and resilience to the otherwise rigid upper Henle layer.

Amino Acid Sequence↗
PubMed2003

Characterization of human keratin-associated protein 1 family members.

Keratin-associated proteins are involved in the formation of the cross-linked network of the keratin-intermediate filament proteins that support hair fibers. In recent years, several keratin-associated protein genes have been identified and become an attractive topic in hair research. More recently, we isolated two cDNA encoding novel members of the human keratin-associated protein 1 family (human keratin-associated protein 1.6 and human keratin-associated protein 1.7), and described their expression in the hair follicle by RNA in situ hybridization. A comparison of human keratin-associated protein 1.6 and human keratin-associated protein 1.7 with other human keratin-associated protein 1 members revealed that keratin-associated protein 1 proteins are fundamentally composed of five distinct domains, and that they can be classified primarily by a striking variation in double cysteine-containing pentapeptide repeats in the repetitive I domain. The sum of the data analyzed suggests that human keratin-associated protein 1 family genes may have arisen mainly through gene duplication of the cysteine-repeat motifs during evolution.

Amino Acid Sequence↗
PubMed2003

Expression of cyclooxygenase isozymes during morphogenesis and cycling of pelage hair follicles in mouse skin: precocious onset of the first catagen phase and alopecia upon cyclooxygenase-2 overexpression.

Cyclooxygenase (COX)-1 and -2 catalyze the key reaction in prostaglandin biosynthesis. Whereas COX-1 is found in most tissues, COX-2, with a few exceptions, is not expressed in normal tissues but becomes transiently induced in the course of inflammatory reactions. In many neoplastic epithelia, COX-2 is constitutively overexpressed. Here we show that COX isozymes are spatiotemporally expressed during morphogenesis of dorsal skin epithelium of NMRI mice. COX-1 and COX-2 mRNA and protein were detected in embryonic and postnatal epidermal tissue by RT-PCR, northern blot, and immunoblot analysis indicating that both isoforms may contribute to prostaglandin production. Being barely detectable in interfollicular epidermis and resting hair follicles of adult mice, COX-2 protein appeared in embryonic skin first in epidermal precursor cells and later on in the basal cells and the peridermal layer of the stratified epidermis. In the course of pelage hair follicle morphogenesis, COX-2 remained expressed in the basal interfollicular compartment and, in addition, became apparent in elongated hair germs and hair pegs and later on in the outer root sheath cells of the distal and proximal hair follicles as well as in basal sebaceous gland cells. During the subsequent synchronous phases of hair cycling, COX-2 expression declined in catagen, was barely detectable in telogen, and was reinduced in the basal outer root sheath and basal sebaceous gland cells of anagen hair follicles. COX-1 immunosignals were detected predominantly in the interfollicular spinous and granular layers of the developing, neonatal, and adult epidermis but not in follicular epithelial cells of developing or cycling hair follicles. Dendritic cells in the interfollicular epidermis and distal hair follicles were also COX-1-positive. Transgenic overexpression of COX-2 under the control of a keratin 5 promoter in basal cells of the interfollicular and follicular epidermis induced a precocious entry into the first catagen stage of postnatal hair follicle cycling and a subsequent disturbance of hair follicle phasing. Furthermore, transgenic mice developed an alopecia. Inhibition of transgenic COX-2 activity by feeding the specific COX-2 inhibitor valdecoxib suppressed the development of alopecia, indicating that COX-2-mediated prostaglandin synthesis is involved in hair follicle biology.

Age Factors↗