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. 2004 Jun 22;101(25):9277-81.
doi: 10.1073/pnas.0402802101. Epub 2004 May 28.

Frizzled6 controls hair patterning in mice

Nini Guo  1 , Charles Hawkins, Jeremy Nathans
Affiliations

Frizzled6 controls hair patterning in mice

Nini Guo et al. Proc Natl Acad Sci U S A. .

Abstract

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.

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Figures

Fig. 1.
Fig. 1.
Targeted mutation of the Fz6 gene and expression of Fz6-nlacZ in skin and hair follicles. (A Upper) Structure of the Fz6 locus. Black rectangles represent the seven exons; in exons 2–7, the shaded areas represent the Fz6 coding region. (Lower Left) Targeting vector. LNL, PGK-neo gene flanked by loxP sites; TK, herpes simplex virus thymidine kinase cassette. (Right) Genotyping of tail DNA with PCR primers specific for the neo-Fz6 junction (KO) or endogenous Fz6 sequences deleted in the targeted allele (Endo). (B) Immunoblot of proteins from P1 skin probed with affinity-purified antibodies directed against the C-terminal 17 aa of Fz6. A band of ≈85 kDa is present in the Fz6(+/+) sample and absent in the Fz6(-/-) sample and is presumed to be Fz6; a crossreacting band of ≈55 kDa is seen in both samples. Protein molecular mass standards from top to bottom are 100, 90, 80, 70, 60, and 50 kDa. (C) X-Gal stain of E14.5 embryos. (Left) Fz6(+/+). (Right) Fz6(+/-). (D and E) X-Gal stain of Fz6(-/-) skin at E16.5; in E, a similar section has also been immunostained for keratin-14 (brown). X-Gal staining is present in the periderm, epidermis, and hair follicles. (F) Enlarged image of the flank of the Fz6(+/-) embryo in C shows X-Gal stain concentrated in developing hair follicles. (G) X-Gal stain of Fz6(+/-) skin at ≈P1. C–G show strong expression of the Fz6-nlacZ reporter in developing epidermis and hair follicles. Fz6(+/-) and Fz6(-/-) show the same pattern of X-Gal staining.
Fig. 2.
Fig. 2.
Altered hair patterns in Fz6(-/-) mice. (A–D)WTand Fz6(-/-) hind feet at approximately P11. (A and C) Left feet. (B and D) Right feet. (E and F) Hematoxylin/eosin staining of frozen sections of skin on the dorsal surface of the hind foot at approximately P3 shows that Fz6(-/-) hair follicles exhibit normal morphology, but, in regions of aberrant patterning (shown in F), they are arranged in divergent orientation. (G–N) Hair on the dorsal surface of the head at approximately P9 shows the heterogeneity of hair patterning among Fz6(-/-) mice. The ears are seen at the lateral edges of each image; rostral is toward the top. (O–R) Hair on the back at approximately P8 shows a rostral to caudal orientation in WT (O), a uniform deviation toward the midline in Fz6(-/-) on a mixed C57BL6 × 129 background (P), and variable deviations on a pure 129 background (Q and R), including a whorl in R. Rostral is toward the top. (S and T) Hair whorls on the neck and chest at approximately P13. The pair of whorls in S is invariant among WT mice. Among Fz6(-/-) mice, the pattern is variable. (U and V) Hair on the dorsal surface of the head at approximately P13. In older mice, longer hair makes the altered hair pattern less apparent.
Fig. 3.
Fig. 3.
Generation of chimeric mice. (A) Diagram of the experimental (Left) and control (Right) embryo aggregation protocols. (B and C) Unstained (B) and X-Gal-stained (C) flatmounts of skin from the head of an albino ICR Fz6(+/+):pigmented C57BL6 × 129 Fz6(-/-) chimeric mouse at approximately P10 shows the independent patterns of tissue chimerism for epidermal cells (X-Gal-stained or unstained) and melanocytes (pigmented or albino). A small amount of tissue shrinkage accompanies the fixation and X-Gal staining procedure. (D) An X-Gal-stained frozen section from the abdomen of a chimeric mouse shows the characteristic heterogeneity of Fz6(-/-) epidermal cells (X-Gal-stained) within single hair follicles. This image also shows, on the scale of individual hair follicles, the independent patterns of tissue chimerism for epidermal cells and melanocytes.
Fig. 4.
Fig. 4.
Hair patterns in embryo aggregation chimeras at approximately P10. From left to right, each horizontal row shows a chimeric mouse, the dorsal surface of one of its hind feet, an unstained flatmount of skin from that foot, a diagram of the unstained flatmount in which each arrow indicates the local hair orientation, and the same flatmount after X-Gal staining. In the diagrams of hair orientation, green and red arrows represent the approximate contributions of albino and pigmented hair, respectively. (A–E) Albino ICR Fz6(+/+):pigmented C57BL6 × 129 Fz6(-/-) chimeras with, from top to bottom, increasing contributions of Fz6(-/-) tissue. (F) A control albino ICR Fz6(+/+):pigmented C57BL6 × 129 Fz6(+/-) chimera shows roughly equal contributions of WT and Fz6(+/-) tissue but exhibits a WT hair pattern. The small boundary of misaligned hairs at lower left in the flatmount in B and at lower right of the flatmount in F is an artifact that arises from flattening the highly curved skin at the lateral edge of the foot.
Fig. 5.
Fig. 5.
Hair patterns among mammals. (A–D) Hair whorls in humans. (A) Single occipital whorl. (B) Frontal whorl with an upsweep of the frontal hair on the opposite side of the forehead. The brother of this subject has the same hair pattern. (C and D) Double occipital whorls in a father (C) and son (D). (E and F) Hair patterns in horses. (E) Most horses have a single whorl between the eyes; an analogous whorl is present in cattle. (F) Hair pattern on the flank at the junction of the hind leg (on the left) and torso (on the right). (G and H) Hair patterns in guinea pigs. Prominent whorls over the surface of the body (G) are referred to as rosettes. (I) In dogs, complex hair patterns are typically present on the upper chest; shown are symmetric whorls on the chest of a Chihuahua. (J) American prairie dog showing one of the two bilaterally symmetric whorls on the upper chest. G, H, and J are reprinted from refs. –, respectively.
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