Disease relevance of Foxn1

• The molecular basis of the characteristic hair growth disorder in nude mice that carry a defective Whn transcription factor gene is unknown [1].

High impact information on Foxn1

• However, subsequent differentiation of primitive precursor cells into subcapsular, cortical, and medullary epithelial cells of the postnatal thymus did depend on activity of the whn gene [2].
• With the use of a targeted disruption of the whn gene, which recapitulates the phenotype of the athymic nude mouse, the WHN transcription factor was shown to be the product of the nude locus [2].
• The pleiotropic nude phenotype which affects the hair, skin, and thymus suggests that whn plays a pivotal role in the development and/or maintenance of these organs [3].
• These results establish whn as a key regulatory factor involved in maintaining the balance between keratinocyte growth and differentiation [3].
• These experiments provide insights into Foxn1-dependent and Foxn1-independent stromal cell development and demonstrate the value of this chimeric approach to analyzing gene function in thymus epithelium [4].

Biological context of Foxn1

• However, the endodermal cells of the thymus/parathyroid rudiments fail to maintain the expression of the parathyroid-specific gene Gcm2 and the thymus-specific gene Foxn1 and subsequently undergo abnormal apoptosis, leading to a complete disappearance of organ primordia by E12 [5].
• Loss-of-function mutations in Whn (Hfh11, Foxn1), a winged-helix/forkhead transcription factor, cause the nude phenotype, which is characterized by the abnormal morphogenesis of the epidermis, hair follicles, and thymus [6].
• Mutations in Foxn1 cause the nude phenotype [7].
• In this paper we describe the production and analysis of mice carrying a 110-kb transgene that encompasses the wild-type Foxn1 genomic locus [7].
• We show that in the hair follicles, transgenic mice with increased Foxn1 gene dosage exhibited increased Foxn1 expression that was restricted correctly to the nascent, post-mitotic cells of the differentiating hair cortex and hair cuticle lineages [7].

Anatomical context of Foxn1

• Here, we provide an overview of what is known on the role of Foxn1 in mammalian skin biology, its expression patterns in the hair follicle, its influence on hair follicle function, and onychocyte differentiation [8].
• To probe the function of postnatal progenitors, a conditional mutant allele of Foxn1 was reverted to wild-type function in single epithelial cells in vivo [9].
• To delineate the biochemical pathway of Whn, we investigated its upstream regulation and downstream effects using primary keratinocytes from wild-type and transgenic mice [6].
• Both Vegf-A alleles were deleted in TECs by a complementation strategy termed nude mouse [mutated in the transcription factor Foxn1 (forkhead box N1)] blastocyst complementation [4].
• The nude mouse lacks functional T cells and other skin defects due to the absence of Foxn1 transcription factor [10].

Associations of Foxn1 with chemical compounds

• IL-7 expression is initiated in the thymic fated domain of the early primordium by embryonic day 11.5 and is expressed in a Foxn1-independent pathway [11].
• The transgenic animals express whn from the involucrin promoter, which is active in keratinocytes undergoing terminal differentiation [6].
• We report here on the use of butylated hydroxytoluene (BHT)-mediated lung injury to demonstrate that HFH-11 protein and RNA levels were markedly increased throughout the period of lung repair [12].
• In this method, one-cell embryos are arrested at metaphase by treatment with nocodazole, and whn exitting from the mitotic phase, two nuclei were formed in a single karyocyte following treatment with 6-dimethylaminopurine (6-DMAP) [13].

Regulatory relationships of Foxn1

• BMP4 also acts directly on the thymic stroma to up-regulate the stroma-specific transcription factor Foxn1 and stroma-expressed chemokines [14].

Other interactions of Foxn1

• The developing third pouch in Hoxa3(+/-)Pax1(-/-) compound mutants initiates normal expression of the parathyroid-specific Gcm2 and thymus-specific Foxn1 genes [15].
• Before the start of differentiation, Whn levels were suppressed by the p42/p44 mitogen-activated protein kinase cascade, and this signaling pathway was rapidly inactivated as differentiation began [6].
• Thus, as keratinocytes commit to terminal differentiation, mitogen-activated protein kinase signaling decreases, which permits the induction of Whn; Whn then activates early features of the differentiation program [6].
• Our results reveal Foxn1 as an essential regulator of tissue assembly in the growing hair shaft and implicate Dsc2 as a downstream effector of this activity [16].
• In an attempt to elucidate the role of the nude mutation on collagen production in skeletal muscles, we have measured collagen levels in several muscles of C57BL/10 nu/nu mice and compared them with mdx nu/nu and Foxn1+/+ control mice [10].

Analytical, diagnostic and therapeutic context of Foxn1

• The mdx mouse bred onto a nude background (Foxn1-/-), to generate mdx nu/nu, serves as a valuable model for the use in muscle cell transplantation or gene therapy studies, to avoid a detrimental immune response [10].
• In situ hybridization of 16 day postcoitus mouse embryos demonstrates that HFH-11 expression is found in the mesenchymal and epithelial cells of the liver, lung, intestine, renal cortex, and urinary tract [17].
• HFH-11 expression is absent in adult hepatocytes, but its expression is reactivated in proliferating hepatocytes at 4, 24, and 48 h after partial hepatectomy [17].
• To identify Whn target genes we isolated RNA populations of wild-type and nude thymic anlagen from embryonic day 12.5 embryos by laser capture microdissection and compared them by gene expression profiling on microarrays representing 22,000 transcripts [18].

References