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• W2040809345 abstract "At present, HOXC13 is the only member of the HOX multigene family that produces a fragile hair phenotype when mutated or overexpressed in mice. To determine whether hair keratin genes are targets for this transcription factor, we analyzed the HOXC13 responsiveness of human hair keratin genes, whose expression matched that of nuclear HOXC13, immunologically revealed in cells of the lower hair-forming compartment of the human anagen hair follicle. We show that HOXC13, but not a homeobox-deleted HOXC13, strongly activated the promoters of the genes, with the respective proximal promoter regions being sufficient for optimal activation. The hair keratin promoters contained numerous putative Hox binding core motifs TAAT, TTAT, and TTAC. Electrophoretic mobility shift assays revealed that HOXC13 bound exclusively to distinct TAAT and TTAT core motifs that were clearly concentrated in the proximal promoter regions. A comparison of the sequences flanking HOXC13 binding and nonbinding core motifs, respectively, allowed the deduction of an extended 8-bp HOXC13 consensus binding sequence TT(A/T)ATNPuPu. Thus, the DNA binding conditions for HOXC13 were distinct from those of other members of the paralogous group 13, i.e. murine Hoxb13 and HOXd13, for which previous investigations yielded the consensus binding sequence TTTA(T/C)NPuPu. Collectively, our data speak for a direct involvement of HOXC13 in the control of hair keratin expression during early trichocyte differentiation. At present, HOXC13 is the only member of the HOX multigene family that produces a fragile hair phenotype when mutated or overexpressed in mice. To determine whether hair keratin genes are targets for this transcription factor, we analyzed the HOXC13 responsiveness of human hair keratin genes, whose expression matched that of nuclear HOXC13, immunologically revealed in cells of the lower hair-forming compartment of the human anagen hair follicle. We show that HOXC13, but not a homeobox-deleted HOXC13, strongly activated the promoters of the genes, with the respective proximal promoter regions being sufficient for optimal activation. The hair keratin promoters contained numerous putative Hox binding core motifs TAAT, TTAT, and TTAC. Electrophoretic mobility shift assays revealed that HOXC13 bound exclusively to distinct TAAT and TTAT core motifs that were clearly concentrated in the proximal promoter regions. A comparison of the sequences flanking HOXC13 binding and nonbinding core motifs, respectively, allowed the deduction of an extended 8-bp HOXC13 consensus binding sequence TT(A/T)ATNPuPu. Thus, the DNA binding conditions for HOXC13 were distinct from those of other members of the paralogous group 13, i.e. murine Hoxb13 and HOXd13, for which previous investigations yielded the consensus binding sequence TTTA(T/C)NPuPu. Collectively, our data speak for a direct involvement of HOXC13 in the control of hair keratin expression during early trichocyte differentiation. in situ hybridization indirect immunofluorescence inner root sheath electrophoretic mobility shift assay 4′,6-diamidino-2-phenylindole Hox genes encode evolutionarily conserved transcription factors that are important gene regulators involved in cell fate determination during embryonic development. In mammals the 39 Hox genes are organized into four separate chromosomal clusters, Hoxathrough Hoxd. Based upon sequence homology and location within a cluster, these genes have been divided into 13 paralogous groups (for reviews see Refs. 1Gehring W.J. Affolter M. Bürglin T. Annu. Rev. Biochem. 1994; 63: 487-526Crossref PubMed Scopus (846) Google Scholar, 2Maconochie M. Nonchev S. Morrison A. Krumlauf R. Annu. Rev. Genet. 1996; 30: 529-556Crossref PubMed Scopus (183) Google Scholar). Due to sequence homologies within the conserved homeobox, Hox genes are related to DrosophilaHOM-C genes with the paralogs 9–13 all being related to the Abd-B gene (3Izpisua-Belmonte J. Falkenstein H. Dollé P. Renucci A. Duboule D. EMBO J. 1991; 10: 2279-2289Crossref PubMed Scopus (273) Google Scholar). During embryonic development, paralogous genes located at the 3′-end of each cluster are activated first, whereas the more 5′-genes are transcribed progressively later. In addition, there is spatial colinearity of position in a cluster such that members of successive paralogous groups have increasingly posterior-anterior limits of expression (4Peterson R.L. Papenbrock T. Davda M.M. Awgulewitsch A. Mech. Dev. 1994; 47: 253-260Crossref PubMed Scopus (87) Google Scholar, 5Capecchi M.R. Cold Spring Harbor Symp. Quant. Biol. 1997; LXII: 273-281Google Scholar). Thus, recent studies on the expression of Hoxc13 during mouse embryogenesis have shown that this 5′-most gene of the Hoxc gene cluster is first expressed at E10.5 in the tail bud (4Peterson R.L. Papenbrock T. Davda M.M. Awgulewitsch A. Mech. Dev. 1994; 47: 253-260Crossref PubMed Scopus (87) Google Scholar, 6Godwin A.R. Capecchi M.R. Genes Dev. 1998; 12: 11-20Crossref PubMed Scopus (197) Google Scholar), followed at E12.5 in the epithelia of the wrist and ankle regions of the limbs in which its expression becomes localized to the developing foot pads and nails at E13.5 (6Godwin A.R. Capecchi M.R. Genes Dev. 1998; 12: 11-20Crossref PubMed Scopus (197) Google Scholar). However, the studies also revealed that at later embryonic stages, Hoxc13 expression obviously deviated from the code of colinearity, as it also occurred in both vibrissae and all body hair follicles, in the filiform papillae of tongue epithelium and in footpad epidermis (6Godwin A.R. Capecchi M.R. Genes Dev. 1998; 12: 11-20Crossref PubMed Scopus (197) Google Scholar). At postnatal day 7, Hoxc13 transcripts in growing anagen hair follicles were seen mainly in the matrix of the hair bulb and the precortical region of the hair shaft and could also be demonstrated at the base of the posterior unit of the filiform tongue papilla (6Godwin A.R. Capecchi M.R. Genes Dev. 1998; 12: 11-20Crossref PubMed Scopus (197) Google Scholar). Correspondingly, besides defects in caudal tail vertebrae, Hoxc13-null mice showed malformation of nails and filiform tongue papillae, and, notwithstanding morphologically normal looking hair follicles, totally lacked vibrissae and pelage hairs due to the premature fracture of hair shafts at the surface of the skin (Ref. 6Godwin A.R. Capecchi M.R. Genes Dev. 1998; 12: 11-20Crossref PubMed Scopus (197) Google Scholar and for reviews see Refs. 7Duboule D. Genes Dev. 1998; 12: 1-4Crossref PubMed Scopus (18) Google Scholar,8Godwin A.R. Capecchi M.R. J. Invest. Dermatol. 1999; 4: 244-247Abstract Full Text PDF Scopus (20) Google Scholar). Since in the mouse, most of these Hoxc13 expressing anatomical regions are also known sites of hair keratin synthesis (9, 10 and references therein), it has been hypothesized that Hoxc13 might possess special functions in hair and filiform papillae development by being involved in the control of hair keratin gene expression (6Godwin A.R. Capecchi M.R. Genes Dev. 1998; 12: 11-20Crossref PubMed Scopus (197) Google Scholar, 7Duboule D. Genes Dev. 1998; 12: 1-4Crossref PubMed Scopus (18) Google Scholar, 8Godwin A.R. Capecchi M.R. J. Invest. Dermatol. 1999; 4: 244-247Abstract Full Text PDF Scopus (20) Google Scholar). In line with this assumption, recent investigations in Hoxc13-overexpressing mice have shown that a variety of hair follicle-specific genes are regulated by this transcription factor (11Tkatchenko A.V. Visconti R.P. Shang L. Papenbrock T. Pruett N.D. Ito T. Ogawa M. Awgulewitsch A. Development. 2001; 128: 1547-1558PubMed Google Scholar).In the past years, our laboratory has elucidated the organization of the human type I and type II hair keratin gene loci and characterized the sequential expression of their members during trichocyte differentiation (12Rogers M.A. Winter H. Wolf C. Heck M. Schweizer J. J. Biol. Chem. 1998; 273: 26683-26691Abstract Full Text Full Text PDF PubMed Scopus (69) Google Scholar, 13Langbein L. Rogers M.A. Winter H. Praetzel S. Beckhaus U. Rackwitz H.R. Schweizer J. J. Biol. Chem. 1999; 274: 19874-19884Abstract Full Text Full Text PDF PubMed Scopus (211) Google Scholar, 14Rogers M.A. Winter H. Langbein L. Wolf C. Schweizer J. J. Invest. Dermatol. 2000; 114: 464-472Abstract Full Text Full Text PDF PubMed Scopus (66) Google Scholar, 15Langbein L. Rogers M.A. Winter H. Praetzel S. Schweizer J. J. Biol. Chem. 2001; 276: 35123-35132Abstract Full Text Full Text PDF PubMed Scopus (237) Google Scholar) Based on this knowledge, we selected three human type I hair keratin genes hHa5, hHa2, andhHa7 as well as the transcribed pseudogeneϕhHaA, whose mRNA expression patterns in the lower hair forming compartment of the human hair follicle (13Langbein L. Rogers M.A. Winter H. Praetzel S. Beckhaus U. Rackwitz H.R. Schweizer J. J. Biol. Chem. 1999; 274: 19874-19884Abstract Full Text Full Text PDF PubMed Scopus (211) Google Scholar, 16Winter H. Langbein L. Krawczak M. Cooper D.N. Jave-Suarez L. Rogers M.A. Praetzel S. Heidt P.J. Schweizer J. Hum. Genet. 2001; 108: 37-42Crossref PubMed Scopus (70) Google Scholar) corresponded to that described for Hoxc13 in mouse hair follicles (6Godwin A.R. Capecchi M.R. Genes Dev. 1998; 12: 11-20Crossref PubMed Scopus (197) Google Scholar), and investigated whether they are target genes for HOXC13. In the present study, we provide strong evidence that these hair keratin genes are transcriptionally up-regulated by HOXC13 primarily via binding of the transcription factor to distinct core recognition motifs, TAAT and TTAT, in the respective proximal promoters.DISCUSSIONHox genes encode transcription factors that act as master switches during embryonic development by controlling the activities of a plethora of downstream target genes. The knowledge about direct Hox target genes is presently poor and most of them have been identified in the fruit fly Drosophila (22Graba Y. Aragnol D. Pradel J. BioEssays. 1997; 19: 379-388Crossref PubMed Scopus (157) Google Scholar). In mammals both the Hoxc8-mediated repression of the osteopontin gene and the HOXA5-controlled activation of the progesterone receptor gene have recently been investigated at the molecular level (23Shi X. Yang X. Chen D. Chang Z. Cao X. J. Biol. Chem. 1999; 274: 13711-13717Abstract Full Text Full Text PDF PubMed Scopus (152) Google Scholar, 24Raman V. Tamori A. Vali M. Zeller K. Korz D. Sukumar S. J. Biol. Chem. 2000; 275: 26551-26555Abstract Full Text Full Text PDF PubMed Scopus (67) Google Scholar). Based on strong evidence indicating a regulatory function of Hoxc13 for hair follicle-specific genes in mice, which either under- or overexpressed this transcription factor (6Godwin A.R. Capecchi M.R. Genes Dev. 1998; 12: 11-20Crossref PubMed Scopus (197) Google Scholar, 11Tkatchenko A.V. Visconti R.P. Shang L. Papenbrock T. Pruett N.D. Ito T. Ogawa M. Awgulewitsch A. Development. 2001; 128: 1547-1558PubMed Google Scholar), the present study was aimed at investigating whether human hair keratin genes are targets for HOXC13. A prerequisite thereof was the demonstration of HOXC13 expression in the adult human anagen hair follicle. Using a HOXC13-specific antiserum, we extended the existing murine Hoxc13 mRNA expression data (6Godwin A.R. Capecchi M.R. Genes Dev. 1998; 12: 11-20Crossref PubMed Scopus (197) Google Scholar) by showing that within the hair-forming compartment of the hair follicle, HOXC13 was strongly present in the nuclei of cells of the entire matrix, including cells lining the dermal papilla, the lower hair cuticle and cortex, in which, however, HOXC13 expression gradually vanished. In beard hairs, cells in the lowermost portion of the central medulla also contained HOXC13 protein in their nuclei. Accordingly, we generated β-galactosidase reporter gene constructs with promoter fragments of type I hair keratin genes hHa2,hHa5, and ϕhHaA, which are expressed in these regions (13Langbein L. Rogers M.A. Winter H. Praetzel S. Beckhaus U. Rackwitz H.R. Schweizer J. J. Biol. Chem. 1999; 274: 19874-19884Abstract Full Text Full Text PDF PubMed Scopus (211) Google Scholar, 15Langbein L. Rogers M.A. Winter H. Praetzel S. Schweizer J. J. Biol. Chem. 2001; 276: 35123-35132Abstract Full Text Full Text PDF PubMed Scopus (237) Google Scholar, 16Winter H. Langbein L. Krawczak M. Cooper D.N. Jave-Suarez L. Rogers M.A. Praetzel S. Heidt P.J. Schweizer J. Hum. Genet. 2001; 108: 37-42Crossref PubMed Scopus (70) Google Scholar), for cotransfection studies with a HOXC13 expression vector. These studies clearly showed that hair keratin promoters strongly activated the reporter gene in the presence of functional but not homeobox deleted HOXC13.Numerous investigations, relying essentially on both DNA site selection protocols and gelshift assays with appropriate oligonucleotides, have provided evidence that Hox proteins may activate or repress their target genes (23Shi X. Yang X. Chen D. Chang Z. Cao X. J. Biol. Chem. 1999; 274: 13711-13717Abstract Full Text Full Text PDF PubMed Scopus (152) Google Scholar, 24Raman V. Tamori A. Vali M. Zeller K. Korz D. Sukumar S. J. Biol. Chem. 2000; 275: 26551-26555Abstract Full Text Full Text PDF PubMed Scopus (67) Google Scholar) primarily via binding of their highly conserved homeobox domain to specific DNA binding motifs. It could be demonstrated that Hox proteins of paralogous groups 1–8 bound preferentially to TAAT core motifs, while both DrosophilaAbd-B protein and Abd-B-like Hox9–13 paralogs exhibited a binding preference for both TTAT and TTAC core motifs (18Ekker S.C. Jackson D.G. von Kessler D.P. Sun B.I. Young K.E. Beachy P.A. EMBO J. 1994; 13: 3551-3560Crossref PubMed Scopus (182) Google Scholar, 19Shen W.F. Montgomery J.C. Rozenfeld S. Moskow J.J. Lawrence H.J. Buchberg A.M. Largman C. Mol. Cell. Biol. 1997; 17: 6448-6458Crossref PubMed Scopus (224) Google Scholar, 20Shen W.F. Rozenfeld S. Lawrence H.J. Largman C. J. Biol. Chem. 1997; 272: 8198-8206Abstract Full Text Full Text PDF PubMed Scopus (125) Google Scholar, 21Shen W.F. Rozenfeld S. Kwong A. Kömüves L.G. Lawrence H.J. Largman C. Mol. Cell. Biol. 1999; 19: 3051-3061Crossref PubMed Scopus (213) Google Scholar). Notwithstanding these apparent binding site preferences, we have screened the endogenous promoters of the functional hair keratin geneshHa5 and hHa2 for all three versions of the core motif. EMSA showed that of the 30 putative core binding motifs collectively present in the two hair keratin promoters, only 10 bound to HOXC13, with six of them being concentrated in the respective proximal promoter regions. In accordance with the existing rules for the site selection preference of Abd-B protein and Hox9–13 paralogs (18Ekker S.C. Jackson D.G. von Kessler D.P. Sun B.I. Young K.E. Beachy P.A. EMBO J. 1994; 13: 3551-3560Crossref PubMed Scopus (182) Google Scholar, 19Shen W.F. Montgomery J.C. Rozenfeld S. Moskow J.J. Lawrence H.J. Buchberg A.M. Largman C. Mol. Cell. Biol. 1997; 17: 6448-6458Crossref PubMed Scopus (224) Google Scholar, 20Shen W.F. Rozenfeld S. Lawrence H.J. Largman C. J. Biol. Chem. 1997; 272: 8198-8206Abstract Full Text Full Text PDF PubMed Scopus (125) Google Scholar), we confirmed a generally strong binding of HOXC13 to three oligonucleotides containing TTAT motifs. However, while virtually no binding was observed for TTAC motifs, surprisingly, HOXC13 clearly bound to seven oligonucleotides containing TAAT motifs. Collectively, the intensities of the TTAT or TAAT HOXC13 binding complexes were comparably strong. This finding clearly contrasted to previous binding studies with the murine Hoxb13 and d13 paralogs, which did not efficiently select for TAAT motifs, but rather exhibited a strong preference for TTAC motifs (19Shen W.F. Montgomery J.C. Rozenfeld S. Moskow J.J. Lawrence H.J. Buchberg A.M. Largman C. Mol. Cell. Biol. 1997; 17: 6448-6458Crossref PubMed Scopus (224) Google Scholar, 20Shen W.F. Rozenfeld S. Lawrence H.J. Largman C. J. Biol. Chem. 1997; 272: 8198-8206Abstract Full Text Full Text PDF PubMed Scopus (125) Google Scholar). Given that HOXC13 binding to both TTAT and TAAT motifs in the hair keratin promoters was not observed with a truncated HOXC13 protein and that in addition, the binding complexes could be specifically supershifted with the HOXC13 antiserum, these data clearly demonstrated a direct binding of HOXC13 to these core motifs in the hair keratin promoters.Previous analyses of the binding sequences for Abd-B-like Hox proteins also revealed distinct base constraints in the regions flanking the core motifs (18Ekker S.C. Jackson D.G. von Kessler D.P. Sun B.I. Young K.E. Beachy P.A. EMBO J. 1994; 13: 3551-3560Crossref PubMed Scopus (182) Google Scholar, 19Shen W.F. Montgomery J.C. Rozenfeld S. Moskow J.J. Lawrence H.J. Buchberg A.M. Largman C. Mol. Cell. Biol. 1997; 17: 6448-6458Crossref PubMed Scopus (224) Google Scholar, 20Shen W.F. Rozenfeld S. Lawrence H.J. Largman C. J. Biol. Chem. 1997; 272: 8198-8206Abstract Full Text Full Text PDF PubMed Scopus (125) Google Scholar, 21Shen W.F. Rozenfeld S. Kwong A. Kömüves L.G. Lawrence H.J. Largman C. Mol. Cell. Biol. 1999; 19: 3051-3061Crossref PubMed Scopus (213) Google Scholar). An inspection of all 10 HOXC13 binding core motifs of the endogenous hHa5 and hHa2 hair keratin promoters showed that these were invariably preceded 5′ by a T and followed 3′ by a variable nucleotide and, as a rule, by two purine residues, thus giving rise to an extended 8-bp consensus-binding sequence TT(A/T)ATNPuPu. Obviously, the T in position 1 is generally mandatory for binding since it was invariably present in oligonucleotides that were site-selected with bothDrosophila Abd-B protein (18Ekker S.C. Jackson D.G. von Kessler D.P. Sun B.I. Young K.E. Beachy P.A. EMBO J. 1994; 13: 3551-3560Crossref PubMed Scopus (182) Google Scholar) and a large number of Abd-B-like Hox proteins (Hoxb9, Hoxa10, Hoxa11, Hoxd12, Hoxd13, Hoxb13 (19Shen W.F. Montgomery J.C. Rozenfeld S. Moskow J.J. Lawrence H.J. Buchberg A.M. Largman C. Mol. Cell. Biol. 1997; 17: 6448-6458Crossref PubMed Scopus (224) Google Scholar, 20Shen W.F. Rozenfeld S. Lawrence H.J. Largman C. J. Biol. Chem. 1997; 272: 8198-8206Abstract Full Text Full Text PDF PubMed Scopus (125) Google Scholar)). Moreover, its selective substitution in the extended HOXC13 consensus binding sequence entailed a complete abolishment of HOXC13 binding. Whether the T upstream of position 1 of the consensus sequence, which preceded 8 of 11 HOXC13 binding sequences (Fig. 7), is involved in binding remains to be seen. Regarding base constraints 3′ to the core motifs, Drosophila Abd-B protein seems to prefer a G in position six of the consensus sequence (18Ekker S.C. Jackson D.G. von Kessler D.P. Sun B.I. Young K.E. Beachy P.A. EMBO J. 1994; 13: 3551-3560Crossref PubMed Scopus (182) Google Scholar), while the above mentioned Hox9–13 proteins and HOXC13 obviously tolerate any base at this position (19Shen W.F. Montgomery J.C. Rozenfeld S. Moskow J.J. Lawrence H.J. Buchberg A.M. Largman C. Mol. Cell. Biol. 1997; 17: 6448-6458Crossref PubMed Scopus (224) Google Scholar, 20Shen W.F. Rozenfeld S. Lawrence H.J. Largman C. J. Biol. Chem. 1997; 272: 8198-8206Abstract Full Text Full Text PDF PubMed Scopus (125) Google Scholar). In contrast, efficient binding of bothDrosophila Abd-B protein and Abd-B-like Hox members requires a purine base in position 7 of the consensus sequence (18–20 and this study). Interestingly, while Drosophila Abd-B protein and Hox9–12 paralogs appear to have a strong preference for a C in position 8 of the consensus sequence (18Ekker S.C. Jackson D.G. von Kessler D.P. Sun B.I. Young K.E. Beachy P.A. EMBO J. 1994; 13: 3551-3560Crossref PubMed Scopus (182) Google Scholar, 19Shen W.F. Montgomery J.C. Rozenfeld S. Moskow J.J. Lawrence H.J. Buchberg A.M. Largman C. Mol. Cell. Biol. 1997; 17: 6448-6458Crossref PubMed Scopus (224) Google Scholar, 20Shen W.F. Rozenfeld S. Lawrence H.J. Largman C. J. Biol. Chem. 1997; 272: 8198-8206Abstract Full Text Full Text PDF PubMed Scopus (125) Google Scholar), murine Hoxd13 and Hoxb13 (19Shen W.F. Montgomery J.C. Rozenfeld S. Moskow J.J. Lawrence H.J. Buchberg A.M. Largman C. Mol. Cell. Biol. 1997; 17: 6448-6458Crossref PubMed Scopus (224) Google Scholar, 20Shen W.F. Rozenfeld S. Lawrence H.J. Largman C. J. Biol. Chem. 1997; 272: 8198-8206Abstract Full Text Full Text PDF PubMed Scopus (125) Google Scholar) as well as human HOXC13, clearly exhibit a higher specificity for a G in this position. Thus the present data on the optimal sequences necessary for binding of the three Hox13 paralogs investigated so far suggest that all require a purine base in position 8 of the consensus sequence, which distinguishes them from the remaining Abd-B-like Hox members. Within the paralogous group 13, however, HOXC13 differs from Hoxb13 and Hoxd13 by the absolute need of a T in position 5, while the others also accept a C. Conversely, while there seems to be an absolute constraint for a T in position 3 for efficient Hoxb13 and Hoxd13 binding, HOXC13 seems to prefer an A, which is normally discriminatory for the binding of Hox1–8 proteins (18Ekker S.C. Jackson D.G. von Kessler D.P. Sun B.I. Young K.E. Beachy P.A. EMBO J. 1994; 13: 3551-3560Crossref PubMed Scopus (182) Google Scholar, 19Shen W.F. Montgomery J.C. Rozenfeld S. Moskow J.J. Lawrence H.J. Buchberg A.M. Largman C. Mol. Cell. Biol. 1997; 17: 6448-6458Crossref PubMed Scopus (224) Google Scholar, 20Shen W.F. Rozenfeld S. Lawrence H.J. Largman C. J. Biol. Chem. 1997; 272: 8198-8206Abstract Full Text Full Text PDF PubMed Scopus (125) Google Scholar).Our transfection studies with reporter gene constructs ofhHa5 and hHa2 promoter fragments have clearly shown that the proximal 200 bp containing varying numbers of HOXC13 binding TAAT and TTAT motifs are sufficient for optimal reporter gene activation by HOXC13. Remarkably, HOXC13-dependent transactivation was also observed for a β-galactosidase construct containing a proximal promoter region of the medullar hair keratin genehHa7,3 which, however, exhibited only one HOXC13 binding TTAATGAG consensus binding sequence. This strongly suggests that both TAAT and TTAT core motifs are involved in HOXC13-mediated reporter gene activation. Whether the relatively low β-galactosidase gene activation observed after cotransfection of pHOXC13 with the 0.2 bp hHa7 promoter construct as compared with that obtained with the corresponding hHa5 andhHa2 promoter constructs is indicative of a hierarchy within TAAT and TTAT core motifs regarding their individual contribution to gene activation can only be resolved by detailed mutation/deletion studies of the critical core motifs of the hair keratin promoters.It is evident that hair keratin promoters would be well suited for studies aimed at investigating the role of cofactors that influence Hox binding. It has been shown that for efficient binding to their consensus sequences, Hox9–10 paralogs either associate with members of Exd/Pbx (25Mann R.S. Chan S.K. Trends Genet. 1996; 12: 258-262Abstract Full Text PDF PubMed Scopus (389) Google Scholar, 26Phelan M.L. Rambaldi I. Featherstone M.S. Mol. Cell. Biol. 1995; 15: 3989-3997Crossref PubMed Scopus (202) Google Scholar) or Meis1 (27Moskow J.J. Bullrich F. Huebner K. Daar I.O. Buchberg A.M. Mol. Cell. Biol. 1995; 15: 5434-5443Crossref PubMed Scopus (283) Google Scholar) family of homeodomain proteins or form triple complexes with these proteins (19Shen W.F. Montgomery J.C. Rozenfeld S. Moskow J.J. Lawrence H.J. Buchberg A.M. Largman C. Mol. Cell. Biol. 1997; 17: 6448-6458Crossref PubMed Scopus (224) Google Scholar, 20Shen W.F. Rozenfeld S. Lawrence H.J. Largman C. J. Biol. Chem. 1997; 272: 8198-8206Abstract Full Text Full Text PDF PubMed Scopus (125) Google Scholar, 21Shen W.F. Rozenfeld S. Kwong A. Kömüves L.G. Lawrence H.J. Largman C. Mol. Cell. Biol. 1999; 19: 3051-3061Crossref PubMed Scopus (213) Google Scholar). In contrast, Hox11–13 paralogs are only able to interact with Meis1, but have been shown to bind equally strong to their consensus sequence in the absence of Meis1(19–21). These studies were performed using oligonucleotides containing either the Edx/Pbx binding consensus sequence ATGAT or the Meis1 binding sequence TGACAG contiguous with a Hox binding sequence (19Shen W.F. Montgomery J.C. Rozenfeld S. Moskow J.J. Lawrence H.J. Buchberg A.M. Largman C. Mol. Cell. Biol. 1997; 17: 6448-6458Crossref PubMed Scopus (224) Google Scholar, 20Shen W.F. Rozenfeld S. Lawrence H.J. Largman C. J. Biol. Chem. 1997; 272: 8198-8206Abstract Full Text Full Text PDF PubMed Scopus (125) Google Scholar, 21Shen W.F. Rozenfeld S. Kwong A. Kömüves L.G. Lawrence H.J. Largman C. Mol. Cell. Biol. 1999; 19: 3051-3061Crossref PubMed Scopus (213) Google Scholar). Since all HOXC13 binding oligonucleotides derived from thehHa5 and hHa2 promoters lacked a Meis1 binding sequence adjacent to the extended HOXC13 binding sequence, none of the two HOXC13 binding complexes consistently observed in our bandshift assays can be attributed to a HOXC13-Meis1 interaction. Meis1 binding consensus sequences are, however, present in both hair keratin promoters. The hHa5 promoter contains two TGACAG motifs, one immediately upstream of the 0.3a5 fragment, the other being located 15 nucleotides upstream of the first motif (see Fig. 4), while in thehHa2 promoter one TGACAG motif lies within the proximal 0.3a2 fragment, 27 nucleotides upstream of the nonbinding TAAT motif 4 (see Fig. 5). Both Meis1 binding studies, and in particular cotransfection studies of appropriately tailored and mutated/deletedhHa2 and hHa5 promoter fragments with a Meis1 expression vector into cells with constitutive HOXC13 expression, will help to better define the relevance of this cofactor for HOXC13 mediated gene activation.Our evidence in vitro for HOXC13-mediated hair keratin gene expression needs to be considered in the context of a recent study that showed that Hoxc13 overexpression in mice led to fragile hairs concomitant with a drastic down-regulation of late, hair-specific genes encoding members of the large multigene family of hair keratin-associated proteins, KAPs (28Powell B.C. Rogers G.E. Jollès P. Zahn H. Hoecker H. Formation and Structure of Human Hair. Birkhäuser Verlag, Basel, Boston, MA1997: 59-148Crossref Google Scholar, 29Rogers M.A. Langbein L. Winter H. Ehmann C. Korn B. Schweizer J. J. Biol. Chem. 2001; 276: 19440-19451Abstract Full Text Full Text PDF PubMed Scopus (90) Google Scholar), while changes in hair keratin gene expression were not reported (11Tkatchenko A.V. Visconti R.P. Shang L. Papenbrock T. Pruett N.D. Ito T. Ogawa M. Awgulewitsch A. Development. 2001; 128: 1547-1558PubMed Google Scholar). We believe that this observation is due to a selective shift of overexpressed Hoxc13 into the mid- to upper cortical compartment (11Tkatchenko A.V. Visconti R.P. Shang L. Papenbrock T. Pruett N.D. Ito T. Ogawa M. Awgulewitsch A. Development. 2001; 128: 1547-1558PubMed Google Scholar), where it may aberrantly affect KAP gene expression. In contrast, our finding that in normal anagen hair follicles, the nuclear HOXC13 expression pattern in the lower hair-forming compartment coincides with that of the hair keratins investigated her, strongly speaks for a gene-activating function of HOXC13 during early trichocyte differentiation. Hox genes encode evolutionarily conserved transcription factors that are important gene regulators involved in cell fate determination during embryonic development. In mammals the 39 Hox genes are organized into four separate chromosomal clusters, Hoxathrough Hoxd. Based upon sequence homology and location within a cluster, these genes have been divided into 13 paralogous groups (for reviews see Refs. 1Gehring W.J. Affolter M. Bürglin T. Annu. Rev. Biochem. 1994; 63: 487-526Crossref PubMed Scopus (846) Google Scholar, 2Maconochie M. Nonchev S. Morrison A. Krumlauf R. Annu. Rev. Genet. 1996; 30: 529-556Crossref PubMed Scopus (183) Google Scholar). Due to sequence homologies within the conserved homeobox, Hox genes are related to DrosophilaHOM-C genes with the paralogs 9–13 all being related to the Abd-B gene (3Izpisua-Belmonte J. Falkenstein H. Dollé P. Renucci A. Duboule D. EMBO J. 1991; 10: 2279-2289Crossref PubMed Scopus (273) Google Scholar). During embryonic development, paralogous genes located at the 3′-end of each cluster are activated first, whereas the more 5′-genes are transcribed progressively later. In addition, there is spatial colinearity of position in a cluster such that members of successive paralogous groups have increasingly posterior-anterior limits of expression (4Peterson R.L. Papenbrock T. Davda M.M. Awgulewitsch A. Mech. Dev. 1994; 47: 253-260Crossref PubMed Scopus (87) Google Scholar, 5Capecchi M.R. Cold Spring Harbor Symp. Quant. Biol. 1997; LXII: 273-281Google Scholar). Thus, recent studies on the expression of Hoxc13 during mouse embryogenesis have shown that this 5′-most gene of the Hoxc gene cluster is first expressed at E10.5 in the tail bud (4Peterson R.L. Papenbrock T. Davda M.M. Awgulewitsch A. Mech. Dev. 1994; 47: 253-260Crossref PubMed Scopus (87) Google Scholar, 6Godwin A.R. Capecchi M.R. Genes Dev. 1998; 12: 11-20Crossref PubMed Scopus (197) Google Scholar), followed at E12.5 in the epithelia of the wrist and ankle regions of the limbs in which its expression becomes localized to the developing foot pads and nails at E13.5 (6Godwin A.R. Capecchi M.R. Genes Dev. 1998; 12: 11-20Crossref PubMed Scopus (197) Google Scholar). However, the studies also revealed that at later embryonic stages, Hoxc13 expression obviously deviated from the code of colinearity, as it also occurred in both vibrissae and all body hair follicles, in the filiform papillae of tongue epithelium and in footpad epidermis (6Godwin A.R. Capecchi M.R. Genes Dev. 1998; 12: 11" @default.
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• W2040809345 title "HOXC13 Is Involved in the Regulation of Human Hair Keratin Gene Expression" @default.
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