The Charles River "hairless" rat mutation maps to chromosome 1: allelic with fuzzy and a likely orthologue of mouse frizzy

Recent evidence has indicated that the recessive mutation affecting hypotrichosis in the Charles River (CR) "hairless" rat does not involve the hairless gene (hr) on rat chromosome 15. To determine if this mutation might be allelic (or orthologous) with any other previously mapped hypotrichosis-generating mutation in mammals, we have produced a panel of backcross rats segregating for the CR hairless rat mutation as well as numerous other markers from throughout the rat genome. Analysis of this panel has located the CR hairless rat's hypotrichosis-generating mutation on chromosome 1, near Myl2, where only the fuzzy mutation in rat (fz) and the frizzy mutation in mouse (fr) have been previously localized. Intercrossing fz/fz and CR hairless rats produced hybrid offspring with abnormal hair, showing that these two rat mutations are allelic. We suggest that the CR hairless rat mutation and fuzzy be renamed frizzy-Charles River (fr(CR)) and frizzy-Harlan (fr(H)), respectively, to reflect their likely orthology with the mouse fr mutation.     

A spontaneous mutation in the desmoglein 4 gene underlies hypotrichosis in a new lanceolate hair rat model

A recessive hairless mutation arose spontaneously in a congenic line of spontaneously hypertensive rats SHR.BN-(D1Mit3-Igf2)/Ipcv. The mutant rats develop generalized alopecia except for partial hair growth on their heads. Affected animals of the congenic line were crossed with LEW rats and randomly bred for several generations. A genome scan in 74 affected and 75 unaffected offspring localized the mutant gene on rat chromosome 18p12, near the marker D18Rat107, which is closely linked to the desmosomal cadherin gene cluster, syntenic to mouse chromosome 18 and human chromosome 18q12. Recently, the mouse and rat phenotypes lah/lah (lanceolate hair) and lah(J)/lah(J)(lanceolate hair-J) were found to be caused by mutations in the desmoglein 4 (Dsg4) gene. Direct sequencing of the Dsg4 gene in the SHR revealed a homozygous C-to-T transition generating a premature termination codon within exon 8 in the affected animals. Further studies on the skin histology in affected rats demonstrated features consistent with a lanceolate hair mutation, providing further support for the crucial role of desmoglein 4 in hair shaft differentiation.     

Analysis of the effects of mutant hairless genes in chimeric mice

The autosomal recessive gene hairless (hr) is responsible for the complete hairlessness in mice homozygous for this gene. Hair shedding that begins at the age of 10 days is caused by an abnormal cycle of hair follicle development disturbed at the catagen stage. This results in enhanced programmed cell death (apoptosis) and ultimately leads to the complete hair follicle destruction and shedding of all hairs by the age of three weeks. To study the phenotypic expression of the hr gene in a chimeric organism, we have obtained 12 chimeric mice hr/hr <--> +/+ by means of aggregation of early embryos hr/hr and +/+. In chimeric mice, the hair shedding has begun two days later than in the hr/hr mice. By day 23 of postnatal development, hairless areas were present on the coat of chimeric mice or the latter were completely hairless depending on the percentage of the hr/hr mutant component. In four chimeras with high content of the mutant component (68-76%), the hair shedding process was similar to that in the hr/hr mice, though it was accomplished two days later. In three chimeras with 48-51% of the mutant component, alternating hairless and hair-covered bands were observed. These data suggest that the hr gene acts in epidermal cells of a hair follicle, because epidermal cell clones in embryonic skin migrate in the lateral-ventral direction coherently and without mixing. However, some chimeras displayed a pattern which was not so clear-cut: the band borders were illegible and hairs partly covered the hairless areas. In some chimeras, the uniform thinning of the coat was observed. Analysis of the effects of the hr mutant gene in chimeric mice differing in the ratio between mutant (hr/hr) and normal (+/+) components in tissues suggests that the hr gene acts in the epidermal cells of the hair follicle. The interactions between cells have an essential effect on the mode and degree of the hr gene expression, which leads to distortion of the "ectodermal" coat pattern in chimeras.     

Molecular Basis for the rhino (hr)Phenotype: A Nonsense Mutation in the MousehairlessGene

The hairless (hr) and rhino (hr^rh) mutations are autosomal recessive allelic mutations that map to mouse Chromosome 14. Both hairless and rhino mice have a number of skin and nail abnormalities and develop a striking form of total alopecia at approximately 3–4 weeks of age. The molecular basis of the hairless mouse phenotype was previously found to be the result of a murine leukemia proviral insertion in intron 6 of thehrgene that resulted in aberrant splicing. In this study, we report a 2-bp substitution in exon 4 of thehrgene in a second allele ofhr,rhino 8J (hr^rh-8J), leading to a nonsense mutation. These findings document the molecular basis of the rhino phenotype for the first time and suggest that rhino is a functional knock-out of thehrgene.     

Congenital atrichia in five Arab Palestinian families resulting from a deletion mutation in the human hairless gene

Congenital atrichia is a rare autosomal recessive disorder of hair development, characterized by complete loss of hair shortly after birth. Evidence of linkage to chromosome 8p12 has been established, implicating the human homolog of the mouse hairless (hr) gene as a candidate gene. We have previously identified missense mutations in families with congenital atrichia. Here, we report the first deletion mutation (2147del C) in exon 9 of the human hairless gene leading to a frameshift and downstream premature termination codon in five Palestinian families of Arab origin. Received: 31 July 1998 / Accepted: 31 August 1998     

Morphological analysis of hair in the hr-2 mutant deer mouse (Peromyscus maniculatus)

Skin from 36 hairless deer mice (Peromyscus maniculatus) homozygous for the recessive hr-2 mutation were analyzed for structural defects in hair and hair loss. Comparison of mutant to wild-type hairs demonstrated characteristic abnormalities in cellular organization, hair shape, length, and fragility. Matings between mutants homozygous for the hr-2 gene and for a second mutation producing hairlessness in deer mice, hr-1, showed that these two genes were nonallelic. Structural abnormalities in hairs associated with the expression of this gene suggest that its primary effect may be on the epidermis.     

The lanceolate hair rat phenotype results from a missense mutation in a calcium coordinating site of the desmoglein 4 gene

Desmosomal cadherins are essential cell adhesion molecules present throughout the epidermis and other organs, whose major function is to provide mechanical integrity and stability to epithelial cells in a wide variety of tissues. We recently identified a novel desmoglein family member, Desmoglein 4 (Dsg4), using a positional cloning approach in two families with localized autosomal recessive hypotrichosis (LAH) and in the lanceolate hair (lah) mouse. In this study, we report cloning and identification of the rat Dsg4 gene, in which we discovered a missense mutation in a naturally occurring lanceolate hair (lah) rat mutant. Phenotypic analysis of lah/lah mutant rats revealed a striking hair shaft defect with the appearance of a lance head within defective hair shafts. The mutation disrupts a critical calcium binding site bridging the second and third extracellular domains of Dsg4, likely disrupting extracellular interactions of the protein.     

Genomic organization and analysis of the <Emphasis Type="Italic">hairless</Emphasis> gene in four hypotrichotic rat strains

More than 25 different hypotrichotic mutations have been described in laboratory rats, yet the molecular basis for these mutations has not been determined for most of these phenotypes. Their similarity to the hairless (hr) mutations described in mice suggests a possible role for the hairless gene in the formation of rat hypotrichotic phenotypes, though whether hr is responsible for these rat phenotypes has yet to be determined. Therefore, in order to understand the basis for the rat hypotrichotic phenotypes and their relationship to the hr gene, we determined the genomic organization of the hr gene and subsequently analyzed the coding sequence in four hypotrichotic rat strains. Analysis revealed that the first two exons of the mouse, monkey, and human hr gene were fused in the rat gene, while the rest of the gene showed strong evolutionary conservation. Despite their designation as hairless, no mutations within the coding sequences were identified, indicating that the hairless phenotype in all four hypotrichotic rat strains are not allelic with hr.     

Supravital Methylene Blue Staining of Piloneural Complexes of Common Fur Hair Follicles in the Rat

Light microscopic observations employing supravital methylene blue staining are presented for piloneural complexes of common fur hairs in the mystacial pad of the rat snout. The investigation revealed anatomical details of piloneural complexes belonging to follicles of both vellus and guard hairs. In the methylene blue stained preparations, different types of palisade-like lanceolate nerve fiber endings could be discriminated. The thicker vellus and thinner guard hairs (hair diameter: 15-25 μm) exhibited a different innervation pattern compared to the thicker guard hairs, and two subtypes of piloneural complexes could be distinguished. Both subtypes were characterized by slightly stained lanceolate endings and the absence of a circular nerve fiber plexus. One subtype, however, showed strongly stained spines originating from the lanceolate endings. A few spines of adjacent lanceolate endings appeared in contact with each other. In the second subtype, these spines were replaced by anastomoses suggesting a delicate terminal nerve fiber network. The moderately stained lanceolate endings located primarily at the follicles of thicker guard hairs (hair diameter: 30-40 μm) showed smooth outlines, but were characterized by the occurrence of an intensely stained additional circular nerve fiber plexus. The differences in the morphology of piloneural complexes associated with the follicles of common fur hairs suggest differences regarding their mechanoreceptive tasks.     

Supravital Methylene Blue Staining of Piloneural Complexes of Common Fur Hair Follicles in the Rat

Light microscopic observations employing supravital methylene blue staining are presented for piloneural complexes of common fur hairs in the mystacial pad of the rat snout. The investigation revealed anatomical details of piloneural complexes belonging to follicles of both vellus and guard hairs. In the methylene blue stained preparations, different types of palisade-like lanceolate nerve fiber endings could be discriminated. The thicker vellus and thinner guard hairs (hair diameter: 15-25 μm) exhibited a different innervation pattern compared to the thicker guard hairs, and two subtypes of piloneural complexes could be distinguished. Both subtypes were characterized by slightly stained lanceolate endings and the absence of a circular nerve fiber plexus. One subtype, however, showed strongly stained spines originating from the lanceolate endings. A few spines of adjacent lanceolate endings appeared in contact with each other. In the second subtype, these spines were replaced by anastomoses suggesting a delicate terminal nerve fiber network. The moderately stained lanceolate endings located primarily at the follicles of thicker guard hairs (hair diameter: 30-40 μm) showed smooth outlines, but were characterized by the occurrence of an intensely stained additional circular nerve fiber plexus. The differences in the morphology of piloneural complexes associated with the follicles of common fur hairs suggest differences regarding their mechanoreceptive tasks.     

Subdivision of mouse vibrissae on an embryological basis, with descriptions of variations in the number and arrangement of sinus hairs and cortical barrels in BALB/c (nu/+; nude, nu/nu) and hairless (hr/hr) strains.

Development of vibrissae was studied in dd/y mouse embryos by scanning electron microscopy. Arrangement of vibrissae and cortical barrels were also studied by light microscopy in adult dd/y, BALB/c(nu/+), nude (BALB/c, nu/nu) and hairless (hr/hr) mice to find genetic or epigenetic variations. Rudiments of vibrissae first appear on Day 12 of pregnancy as longitudinal ridges on the developing muzzle, and each hair rudiment is represented by a dome on the ridges. The dorsal two rows (A and B; Woolsey and Van der Loos, '70) of mystacial vibrissae are on the lateral nasal prominence, while the ventral three (C, D and E) are on the maxillary prominence. Smaller hairs of mystacial vibrissae appear at the labial part of the maxillary prominenceon Day 13. The rudiments of rhinal hairs also appear at this stage on the part of the muzzle derived from the medial nasal prominence. Thus the so-called mystacial vibrissae should be subdivided into three (or 4, including the rhinal) groups on an embryological basis. They are the lateral nasal, the maxillary and the labial. A supernumerary sinus hair and a corresponding barrel was observed between D and C rows uni-or bilaterally in one third of individuals of BALB/c, nude and hairless mice. It is suggested that supernumerary hairs tend to occur between the groups of hairs as defined above. In nude and hairless mice small barrels representing labial hairs are diminished in number. The number of hair follicles, however, is normal.     

TOMATO TRICHOMES AND MUTATIONS AFFECTING THEIR DEVELOPMENT

A new trichome type for the genus Lycopersicon is described in L. esculentum Mill. It is a short (0.03–0.08 mm), pendant, glandular hair with a club-shaped head consisting of 8–12 cells. Two previously described “hairless” mutations were examined microscopically. One, hl, does not affect the frequency of hairs nor the number of cells per hair, but causes abnormal enlargement of the stalk cells of all hair types, and thus produces shortened, extremely bent and twisted hairs. Observations on the time of action of this gene indicate that in trichome development two to four cell divisions occur prior to any appreciable cell enlargement. The second mutation, h, affects only the large type of trichome. This mutation effects a developmental shift from trichome to stomatal apparatus at the apex of the multicellular base normally supporting the large trichomes.     

Genomic organization of the human hairless gene (HR) and identification of a mutation underlying congenital atrichia in an Arab Palestinian family

Congenital atrichia is a rare form of hereditary human hair loss, characterized by the complete shedding of hair shortly after birth, together with the formation of papular lesions on the skin. Recently, we cloned the human homolog of the mouse hairless gene and identified pathogenic mutations in several families with inherited congenital atrichia. Here, we present the genomic organization of the human hairless gene (HGMW-approved symbol HR), which spans over 14 kb on chromosome 8p12 and is organized into 19 exons. In addition, we report the identification of a 22-bp deletion mutation in exon 3 of the hairless gene in a large consanguineous Arab Palestinian family from a village near Jerusalem, Israel. These findings extend the body of evidence implicating mutations in the hairless gene as an underlying cause of congenital atrichia in humans.     

Curly bare (cub), a new mouse mutation on chromosome 11 causing skin and hair abnormalities,and a modifier gene (mcub) on chromosome 5

In the outcrossing of a new recessive mouse mutation causing hair loss, a new wavy-coated phenotype appeared. The two distinct phenotypes were shown to be alternative manifestations of the same gene mutation and attributable to a single modifier locus. The new mutation, curly bare (cub), was mapped to distal Chr 11 and the modifier (mcub) was mapped to Chr 5. When homozygous for the recessive mcub allele, cub/cub mice appear hairless. A single copy of the dominant Mcub allele confers a full, curly coat in cub/cub mice. Reciprocal transfer of full-thickness skin grafts between mutant and control animals showed that the skin phenotype was tissue autonomous. The hairless cub/cub mcub/mcub mice show normal contact sensitivity responses to oxazolone. The similarity of the wavy coat phenotype to those of Tgfa and Egfr mutations and the map positions of cub and mcub suggest candidate genes that interact in the EGF receptor signal transduction pathway.     

Maternal methyl supplements affect the phenotypic variation of the <Emphasis Type="Italic">agouti</Emphasis> gene in the offspring of rats with different behavioral types

The effects of selection of agouti rats (with genotype AAHH) on the tame and aggressive behavior and dietary methyl given to females from the eighth day of pregnancy to the fifth day after the birth of the offspring on the intensity of the agouti coat color in the offspring have been studied. The morphometric parameters of hair determining the darkness of the agouti color (the total length of guard hairs, the lengths of their eumelanin end and pheomelanin band, the ratio between the lengths of the eumelanin and pheomelanin portions of the hair, the total length of the awn hairs, and the relative length of their widened “lanceolate” upper end) have been compared. It has been found that selection of agouti rats for aggressive behavior is accompanied by darkening of the coat color compared to tame rats due to an increase in the ratio of the length of the black eumelanin end of the guard hairs to the length of the yellow pheomelanin band. Methyl-containing additives to the diet of females affect the intensity of the agouti coat color in the offsprings with both types of behavior, but to different extents. Aggressive offspring is more sensitive to the mother’s methyl-containing diet: the percentage of animals that are darker than control rats is higher among aggressive animals than among tame ones due to a greater increase in the ratio between dark and light portions of hairs. The possible mechanisms of differences in the phenotypic modifications of coat color in control and experimental agouti rats with different types of behavior are discussed.