Hair whorls and other macroscopic hair patterns are found in a variety of mammalian species, including humans. We show here that Frizzled6 (Fz6), one member of a large family of integral membrane Wnt receptors, controls macroscopic hair patterning in the mouse. Fz6 is expressed in the skin and hair follicles, and targeted deletion of the Fz6 gene produces stereotyped whorls on the hind feet, variable whorls and tufts on the head, and misorientation of hairs on the torso. Embryo chimera experiments imply that Fz6 acts locally to control or propagate the macroscopic hair pattern and that epithelial cells rather than melanocytes are the source of Fz6-dependent signaling. The Fz6 phenotype strongly resembles the wing-hair and bristle patterning defects observed in Drosophila frizzled mutants. These data imply that hair patterning in mammals uses a Fz-dependent tissue polarity system similar to the one that patterns the Drosophila cuticle.T he founding member of the Frizzled (Fz) family was identified in Drosophila as a gene required for producing the correct orientation of cuticular bristles and hairs, a process referred to as tissue or planar polarity (1, 2). Fz family members have subsequently been found throughout the animal kingdom (3), and experiments in cell culture and in Drosophila have shown that they function as Wnt receptors (4-8). Current evidence indicates that Fzs can signal through at least three distinct pathways: the ''canonical Wnt pathway'' (involving stabilization of -catenin and selective gene activation), a rho͞jun kinase pathway, and a G protein pathway that mobilizes calcium (9). At present, the identity of the ligand(s) involved in tissue polarity signaling is unknown.Thus far, in vivo functions have been defined for only three of the 10 mammalian Fz genes. Loss of Fz3 produces defects in axonal development and pathfinding in the CNS (10, 11); loss of Fz4 produces progressive cerebellar degeneration, esophageal enlargement, atrophy of the stria vascularis in the inner ear, and defective development of the retinal vasculature (12-14); and loss of Fz5 produces defects in yolk sac and placental angiogenesis (15). Whether any of these diverse phenotypes involves the tissue polarity pathway is unclear. However, a bona fide mammalian tissue polarity system almost certainly exists because (i) there are mammalian orthologues for most, if not all, of the Drosophila genes implicated in tissue polarity, and (ii) orientation defects are observed in developing auditory hair cells in mice defective in any of three of these orthologues (Vangl2, Scrb1, and Celsr1; refs. 16 and 17), and similar defects can be induced by application of soluble Wnt antagonists in explant culture (18).In this paper, we show that the phenotype associated with targeted mutation in the mouse Fz6 gene strongly resembles the wing hair and bristle patterning defects observed in Drosophila fz mutants. These data imply that hair patterning in mammals uses an Fz-dependent tissue polarity system similar to the one that patterns the Dro...
Vascular permeability plays a key role in a wide array of lifethreatening and sight-threatening diseases. Vascular endothelial growth factor can increase vascular permeability. Using a model system for nonproliferative diabetic retinopathy, we found that pigment epithelium-derived factor (PEDF) effectively abated vascular endothelial growth factor-induced vascular permeability. A 44-amino acid region of PEDF was sufficient to confer the antivasopermeability activity. Additionally, we identified four amino acids (glutamate-101, isoleucine-103, leucine-112, and serine-115) critical for this activity. PEDF, or a derivative, could potentially abate or restore vision loss from diabetic macular edema. Furthermore, PEDF may represent a superior therapeutic approach to sepsis-associated hypotension, nephrotic syndrome, and other sight-threatening and life-threatening diseases resulting from excessive vascular permeability.
Periciliary fluid balance is maintained by the coordination of sodium and chloride channels in the apical membranes of the airways. In the absence of the cystic fibrosis transmembrane regulator (CFTR), chloride secretion is diminished and sodium reabsorption exaggerated. ClC-2, a pH- and voltage-dependent chloride channel, is present on the apical membranes of airway epithelial cells. We hypothesized that ClC-2 agonists would provide a parallel pathway for chloride secretion. Using nasal potential difference (NPD) measurements, we quantified lubiprostone-mediated Cl(-) transport in sedated cystic fibrosis null (gut-corrected), C57Bl/6, and A/J mice during nasal perfusion of lubiprostone (a putative ClC-2 agonist). Baseline, amiloride-inhibited, chloride-free gluconate-substituted Ringer with amiloride and low-chloride Ringer plus lubiprostone (at increasing concentrations of lubiprostone) were perfused, and the NPD was continuously recorded. A clear dose-response relationship was detected in all murine strains. The magnitude of the NPD response to 20 muM lubiprostone was -5.8 +/- 2.1 mV (CF, n = 12), -8.1 +/- 2.6 mV (C57Bl/6 wild-type, n = 12), and -5.3 +/- 1.2 mV (AJ wild-type, n = 8). A cohort of ClC-2 knockout mice did not respond to 20 muM lubiprostone (n = 6, P = 0.27). In C57Bl/6 mice, inhibition of CFTR with topical application of CFTR inhibitor-172 did not abolish the lubiprostone response, thus confirming the response seen is independent of CFTR regulation. RT-PCR confirmed expression of ClC-2 mRNA in murine lung homogenate. The direct application of lubiprostone in the CF murine nasal airway restores nearly normal levels of chloride secretion in nasal epithelia.
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