The gene for mouse epidermal filaggrin precursor. Its partial characterization, expression, and sequence of a repeating filaggrin unit.

Rothnagel, Joseph A.; Mehrel, Thomas; Idler, William W.; Roop, Dennis R.; Steinert, Peter M.

doi:10.1016/s0021-9258(18)47775-7

Cited by 92 publications

(16 citation statements)

References 31 publications

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“…Structure of the mouse pro®laggrin gene Restriction mapping and southern blot analysis was used to identify ®laggrin sequences within the P1/2900 clone isolated from the mouse genomic library (data not shown). A coding probe generated from the 750 bp ®laggrin repeat (Rothnagel and Steinert, 1990) detected a single high molecular weight fragment (> 30 kb) in an EcoR1 digest of the P1/2900 clone, which was of similar size to that observed in a genomic DNA digest (Rothnagel et al, 1987). The same band was also identi®ed using a 3¢ noncoding probe, indicating that this fragment most probably contained the entire gene.…”

Section: Resultsmentioning

confidence: 82%

“…Comparison of the mouse pro®laggrin gene in the P1/2900 clone with the published sequence for mouse ®laggrin and the 3¢ end of the pro®laggrin gene (Rothnagel et al, 1987;Rothnagel and Steinert, 1990) showed only minor variation between these sequences. The mapping analysis did show differences in the number of ®laggrin repeats, however (12 in the P1/2900 clone versus 20 in the cosmid clone of the earlier study), and in their sequential order (see Fig 1 and Rothnagel and Steinert, 1990).…”

Section: Discussionmentioning

confidence: 91%

“…The DNA fragments were immobilized on Hybond-N or NX nylon membranes (Amersham, Sydney, Australia) according to the manufacturer's instructions. A 750 bp ®laggrin repeat probe (type B; Rothnagel and Steinert, 1990) and a 180 bp 3¢ noncoding probe (Rothnagel et al, 1987) were labeled with [a 32 P]dCTP using the RadPrime DNA labeling system (Gibco BRL, Gaithersburg, MD). Hybridization and washing were carried out using established protocols (Sambrook et al, 1989).…”

Section: Methodsmentioning

confidence: 99%

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Characterization of Mouse Profilaggrin: Evidence for Nuclear Engulfment and Translocation of the Profilaggrin B-Domain during Epidermal Differentiation

Zhang¹,

Karunaratne

Kessler

et al. 2002

Journal of Investigative Dermatology

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Filaggrin is a keratin filament associated protein that is expressed in granular layer keratinocytes and derived by sequential proteolysis from a polyprotein precursor termed profilaggrin. Depending on the species, each profilaggrin molecule contains between 10 and 20 filaggrin subunits organized as tandem repeats with a calcium-binding domain at the N- terminal end. We now report the characterization of the complete mouse gene. The structural organization of the mouse gene is identical to the human profilaggrin gene and consists of three exons with a 4 kb intron within the 5' noncoding region and a 1.7 kb intron separating the sequences encoding the calcium-binding EF-hand motifs. A processed pseudogene was found embedded within the second intron. The third and largest exon encodes the second EF-hand, a basic domain (designated the B-domain) followed by 12 filaggrin repeats and a unique C-terminal tail domain. A polyclonal antibody raised against the conceptually translated sequence of the B-domain specifically stained keratohyalin granules and colocalized with a filaggrin antibody in granular layer cells. In upper granular layer cells, B-domain containing keratohyalin granules were in close apposition to the nucleus and, in some cells, appeared to be completely engulfed by the nucleus. In transition layer cells, B-domain staining was evident in the nucleus whereas filaggrin staining remained cytoplasmic. Nuclear staining of the B-domain was also observed in primary mouse keratinocytes induced to differentiate. This study has also revealed significant sequence homology between the mouse and human promoter sequences and in the calcium-binding domain but the remainder of the protein-coding region shows substantial divergence.

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Section: Resultsmentioning

confidence: 82%

Section: Discussionmentioning

confidence: 91%

Section: Methodsmentioning

confidence: 99%

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Characterization of Mouse Profilaggrin: Evidence for Nuclear Engulfment and Translocation of the Profilaggrin B-Domain during Epidermal Differentiation

Zhang¹,

Karunaratne

Kessler

et al. 2002

Journal of Investigative Dermatology

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“…At E15.5, the epidermis forms an intermediate layer between the basal layer and the periderm, which corresponds to the adult spinous layer and is marked by the onset of K1 and K10 expression (Bickenbach et al, 1995). Loricrin and ¢laggrin are ¢rst expressed between E16.5 and E17.5 as the granular layer and stratum corneum form, creating a water impermeable barrier (Rothnagel et al, 1987;Mehrel et al, 1990;Bickenbach et al, 1995). At E18.5 the epidermis is fully stra-ti¢ed and the periderm is shed.…”

Section: Epidermal Developmentmentioning

confidence: 99%

Epidermal Differentiation: Transgenic/Knockout Mouse Models Reveal Genes Involved in Stem Cell Fate Decisions and Commitment to Differentiation

Koster

Huntzinger

Roop

2002

Journal of Investigative Dermatology Symposium Proceedings

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Epidermal development and differentiation are similar processes and therefore the study of one is likely to provide insight into the other. The signaling cascades required for epidermal differentiation are largely unknown. Recent evidence, however, has implicated two proteins, p63 and c-Myc, in different stages of epidermal development and differentiation. p63 was shown to be required for embryonic epidermal development. Mice lacking p63 do not develop stratified epithelia and appendages suggesting a role for p63 in the commitment to squamous epithelial lineages. Subsequent stem cell fate decisions are required to form the different structures of stratified epithelia including hair follicles, sebaceous glands, and epidermis. Several genes of the Wnt signaling pathway have been implicated in this process, including c-Myc, a downstream target of the Wnt pathway. Interestingly, targeted overexpression of c-Myc in the basal layer of the epidermis results in an increase in sebaceous gland size and number at the expense of hair follicles. This suggests that c-Myc promotes differentiation of epidermal stem cells into sebaceous glands. In this review, we discuss transgenic/knockout mouse models that have provided evidence linking c-Myc and p63 to different stages of epidermal development and differentiation.

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“…Only the ®rst ®laggrin unit of 250 amino acids is shown. Like other mammalian pro®laggrins, the C-terminal end of the protein contains a truncated ®laggrin unit and unique peptide of 23 amino acids(Rothnagel et al, 1987; GenBank Accession Number J03458). The protein motifs located in the mouse A and B domains are indicated.…”

mentioning

confidence: 99%

Functional Analysis of the Profilaggrin N-Terminal Peptide: Identification of Domains that Regulate Nuclear and Cytoplasmic Distribution

Pearton

Dale

Presland

2002

Journal of Investigative Dermatology

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Profilaggrin is expressed in the differentiating granular layer of epidermis and other stratified epithelia, where it forms a major component of cytoplasmic keratohyalin granules. It consists of two distinct domains, an N-terminal S100-like Ca2+- binding domain containing two EF-hands and multiple filaggrin units that aggregate keratin filaments in the stratum corneum. Here, we report structure-function studies of the N-terminal peptide from mouse, human, and rat profilaggrin. The profilaggrin N- terminal peptides of all species contain two S100-like EF-hands, bipartite nuclear localization sequences, and proprotein convertase cleavage sites. The nuclear localization signals in human and mouse profilaggrin were shown to be functional by transfection of epithelial cells and depended on the absence of filaggrin sequences. The nuclear localization of the processed (free) N-terminal peptide of human profilaggrin is consistent with immunolocalization findings in normal human skin and in parakeratotic skin disorders, which exhibit nuclear staining of granular and/or cornified layers. The mouse profilaggrin N-terminus undergoes proteolytic processing in two steps, first releasing an N-terminal peptide containing some filaggrin sequence and finally the free N-terminus of 28-30 kDa; these peptides have cytoplasmic and nuclear distributions, respectively, when expressed in transfected cells. The N-terminal processing may occur prior to or simultaneously with the proteolytic processing of the polyfilaggrin domain. The nuclear accumulation of the profilaggrin N-terminal peptide in epidermis and in transfected cells strongly suggests a calcium-dependent nuclear function for the profilaggrin N-terminus during epidermal terminal differentia tion when the free N-terminus is released from profilaggrin by specific proteolysis.

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The gene for mouse epidermal filaggrin precursor. Its partial characterization, expression, and sequence of a repeating filaggrin unit.

Cited by 92 publications

References 31 publications

Characterization of Mouse Profilaggrin: Evidence for Nuclear Engulfment and Translocation of the Profilaggrin B-Domain during Epidermal Differentiation

Characterization of Mouse Profilaggrin: Evidence for Nuclear Engulfment and Translocation of the Profilaggrin B-Domain during Epidermal Differentiation

Epidermal Differentiation: Transgenic/Knockout Mouse Models Reveal Genes Involved in Stem Cell Fate Decisions and Commitment to Differentiation

Functional Analysis of the Profilaggrin N-Terminal Peptide: Identification of Domains that Regulate Nuclear and Cytoplasmic Distribution

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