Overexpression of Hr links excessive induction of Wnt signaling to Marie Unna hereditary hypotrichosis

Abstract

Marie Unna hereditary hypotrichosis (MUHH) is a rare autosomal dominant hair disorder. Through the study of a mouse model, we identified a mutation in the 5'-untranslated region of the hairless (HR) gene in patients with MUHH in a Caucasian family. The corresponding mutation, named 'hairpoor', was found in mutant mice that were generated through N-ethyl-N-nitrosourea mutagenesis. Hairpoor mouse mutants display partial hair loss at an early age and progress to near alopecia, which resembles the MUHH phenotype. This mutation conferred overexpression of HR through translational derepression and, in turn, decreased the expression of Sfrp2, an inhibitor of the Wnt signaling pathway. This study indicates that the gain in function of HR also results in alopecia, as seen with the loss of function of HR, via abnormal upregulation of the Wnt signaling pathway.

Human Cannabinoid Pharmacokinetics

“…Thus, the pharmacokinetics of oral THC is of great importance to the successful application of new therapeutic approaches. In a study of the plasma concentrations of THC, 11-OH-THC, and THC-COOH in 17 volunteers upon intake of a single Marinol® capsule (10 mg of THC), mean peak concentrations of 3.8 ng/ml of THC (range 1.1 −12.7 ng/ml), 3.4 ng/ml of 11-OH-THC (range 1.2−5.6 ng/ml), and 26 ng/ml of THC-COOH (range 14−46 ng/ml) were found 1−2 h after ingestion [28]. Similar THC and 11-OH-THC concentrations were observed with consistently higher THC-COOH concentrations.…”

Downregulation of Foxe1 by HR suppresses Msx1 expression in the hair follicles of HrHpmice

“…HR also transcriptionally regulates several Wnt signaling associated genes, especially those such as Sostdc1, Sfrp1, Sfrp2, and Wnt Inhibitory Facotr 1 (Wif1), which repress Wnt signaling (8,9,13). Moreover, the downregulation of these genes by HR causes Wnt pathway induction, which is critical for the proliferation and differentiation of HF cells and cyclic regeneration of the HF (8,9).…”

“…Immunohistochemistry analysis was performed as described previously (8). The primary antibody against K14 was used (1：1,000; Covance) and counterstained with DAPI.…”

“…Hairpoor homozygote mice are naked at birth. MUHH patients and Hairpoor mice exhibit similar mutations: in each case a single-nucleotide substitution in the second upstream open reading frame of the Hairless (Hr) gene results in a gain-of-function mutation that leads to overexpression of HR in skin during HF development (8).…”

“…HR is a transcriptional corepressor that interacts with transcription factors such as the Vitamin D Receptor, Thyroid Hormone Receptor, and Retinoic-Acid Related Orphan Receptor to downregulate expression of their respective target genes (10)(11)(12). In particular, HR stimulates Wnt signaling via the suppression of its inhibitors, such as Secreted Frizzled-related Protein 2 (Sfrp2) and Sclerostin-Domain Containing 1 (Sostdc1) (8,9).…”