- Research article
- Open Access
The juvenile alopecia mutation (jal) maps to mouse Chromosome 2, and is an allele of GATA binding protein 3 (Gata3)
- Francisco Ramirez†1,
- Aaron M Feliciano†1,
- Elisabeth B Adkins1,
- Kevin M Child1,
- Legairre A Radden II1,
- Alexis Salas1,
- Nelson Vila-Santana1,
- José M Horák1,
- Samantha R Hughes1,
- Damek V Spacek1 and
- Thomas R King1Email author
© Ramirez et al.; licensee BioMed Central Ltd. 2013
- Received: 12 October 2012
- Accepted: 22 March 2013
- Published: 9 May 2013
Mice homozygous for the juvenile alopecia mutation (jal) display patches of hair loss that appear as soon as hair develops in the neonatal period and persist throughout life. Although a report initially describing this mouse variant suggested that jal maps to mouse Chromosome 13, our preliminary mapping analysis did not support that claim.
To map jal to a particular mouse chromosome, we produced a 103-member intraspecific backcross panel that segregated for jal, and typed it for 93 PCR-scorable, microsatellite markers that are located throughout the mouse genome. Only markers from the centromeric tip of Chromosome 2 failed to segregate independently from jal, suggesting that jal resides in that region. To more precisely define jal’s location, we characterized a second, 374-member backcross panel for the inheritance of five microsatellite markers from proximal Chromosome 2. This analysis restricted jal’s position between D2Mit359 and D2Mit80, an interval that includes Il2ra (for interleukin 2 receptor, alpha chain), a gene that is known to be associated with alopecia areata in humans. Complementation testing with an engineered null allele of Il2ra, however, showed that jal is a mutation in a distinct gene. To further refine the location of jal, the 374-member panel was typed for a set of four single-nucleotide markers located between D2Mit359 and D2Mit80, identifying a 0.55 Mb interval where jal must lie. This span includes ten genes—only one of which, Gata3 (for GATA binding protein 3)—is known to be expressed in skin. Complementation testing between jal and a Gata3 null allele produced doubly heterozygous, phenotypically mutant offspring.
The results presented indicate that the jal mutation is a mutant allele of the Gata3 gene on mouse Chromosome 2. We therefore recommend that the jal designation be changed to Gata3 jal , and suggest that this mouse variant may provide an animal model for at least some forms of focal alopecia that have their primary defect in the hair follicle and lack an inflammatory component.
- Mouse model, Focal alopecia, Positional candidate approach, Il2ra
- Gata3, Complementation testing
Here, we describe the completed molecular-genetic analysis of a pair of large backcross families that allowed us to locate jal on mouse Chr 2, and then restrict its location to a small, defined interval at the centromeric tip. In addition, we describe complementation testing between jal and engineered null alleles of two co-localizing candidate genes, one of which (Gata3, for GATA binding protein 3) we identify as the likely basis of the juvenile alopecia phenotype in mice.
Mice from the standard inbred strains C57BL/6 J, C3H/HeJ, A/J, as well as inbred C3H/HeJ-jal/J mice were obtained from The Jackson Laboratory (Bar Harbor, ME, USA). Mice homozygous for the mutant jal allele were most reliably identified by vibrissae defects that are first evident shortly after birth. By two weeks of age, homozygotes present with distinct patches of hair loss (most often on the dorsal surface) that persist throughout life (see Figure 1). The amount of body surface affected varies widely among homozygous individuals (from less than 5% to greater than 95% [see Additional file 1]), even within the inbred C3H/HeJ-jal strain. While both male and female jal/jal homozygotes are fertile, we have maintained the C3H/HeJ-jal line since 2009 by crossing heterozygous females with homozygous males, to produce segregating litters.
Mice carrying a targeted mutation in the interleukin 2 receptor, alpha chain gene (Il2ra tm1Dw ) were also obtained from The Jackson Laboratory. The creation of the Il2ra tm1Dw loss-of-function allele is described by Willerford et al.. In brief, these investigators used homologous recombination to replace a 5.5 kb segment of the Il2ra gene which contains Exons 2 and 3 and encodes the interleukin 2 binding site  with a phosphoglycerate kinase (PGK)-neomycin resistance (neo) cassette. Mice carrying a targeted mutation in the GATA binding protein 3 gene (Gata3 tm1Gsv ) were kindly donated by Dr. James Douglas Engel (University of Michigan, Ann Arbor, MI, USA). The creation of the Gata3 tm1Gsv loss-of-function/reporter allele is described by van Doorninck et al.. In brief, these investigators replaced 157 bp in Exon 2, including the start codon, with a nuclear localization signal (nls)-lacZ fusion cassette, followed by a PGK-hygromycin resistance (hyg) cassette.
All studies were in compliance with protocols approved by the Institutional Care and Use Committee (IACUC) at Central Connecticut State University (New Britain, CT, USA).
DNA isolation and analysis
Genomic DNA was isolated from 3 mm tail tip biopsies taken from two-week-old mice, using Nucleospin kits from BD Biosciences (Palo Alto, CA, USA). The polymerase chain reaction (PCR) was performed using the Titanium PCR kit from Clontech (Palo Alto, CA, USA). Oligonucleotide primers for PCR were synthesized by Invitrogen (Carlsbad, CA, USA), based on sequence information from online sources [15, 16]. In addition to standard, PCR-scorable, microsatellite markers , we also assayed 4 markers based on single-nucleotide polymorphisms that have been reported to differ between the A/J and C3H/HeJ strains [15, 16]. These markers, designated herein as SNP1-4, are described in detail in Additional file 2 and Additional file 3. To distinguish between Il2ra tm1Dw carriers and wild type mice, we used the 4-primer PCR assay recommended by the mouse supplier (The Jackson Laboratory). Two of these primers (5′CTGTGTCTGTATGACCCACC 3′, and 5′ CAGGAGTTTCCTAAGCAACG 3′) correspond to Exon 2 of Il2ra, which in the mutant has been replaced with a PGK-neo cassette, and yield a 280 bp amplimer with wild type DNA templates. The other two primers (5′ CTTGGGTGGAGAGGCTATTC 3′, and 5′AGGTGAGATGACAGGAGATC 3′) correspond to the neo gene, and direct the amplification of a 280 bp amplimer from mutant DNA templates. To distinguish between Gata3 tm1Gsv carriers and wild type mice, we used a 3-primer PCR assay of our own design. For this test, one primer-pair (forward primer, 5′ CCCTAAACCCTCCTTTTTGC 3′, and reverse primer 5′ GATACCTCTGCACCGTAGCC 3′) flanked the site of the engineered disruption in Exon 2, and produced a 399 bp amplimer with wild type templates; that forward primer and second reverse primer (5′ GTTTTCCCAGTCACGACGTT 3′), based on sequences within in lacZ, yielded a 320 bp amplimer that is specific to the Gata3 tm1Gsv allele.
PCR products plus 2 ul loading buffer (bromophenol blue in 20% Tris-buffered sucrose) were electrophoresed through 3.25% NuSeive 3:1 agarose gels (Lonza, Rockland, ME, USA). Gels were stained with ethidium bromide (0.5 ug/mL) and photographed under ultraviolet light. For sequence analysis, about 1.5 ug of individual PCR amplimers were concentrated into a 30 ul volume using QIAquick PCR Purification kits (Qiagen, Valencia, CA, USA). Purified amplimers were shipped to SeqWright, Inc. (Houston, TX, USA) for primer-extension analysis.
Total RNA was isolated from skin and thymus samples taken from 1-month-old mutant and wild type mice mice using the Nucleospin® RNA L kit by Macherey-Nagel (Easton, PA, USA). cDNA was generated using the SMARTer™ RACE cDNA amplification kit (Clontech Laboratories). To amplify Gata3-specific cDNA, primer pairs that flanked exon junction boundaries were used in “step-down” PCR reactions. The products of this initial reaction were diluted 1:10 in Tricine-KOH buffer (10 mM, pH 8.5) plus 1 mM EDTA, and were amplified again in standard PCR reactions using the same or nested primer pairs. Second-round amplimers were purified (as described above) and shipped to SeqWright, Inc., for primer-extension sequencing.
Mapping jalto a mouse chromosome
To determine if jal might be carried on the mouse X chromosome, we conducted reciprocal crosses of homozygous mutant mice with wild type mice from the C57BL/6 J strain. Since the F1 progeny of both genders were phenotypically wild type [see Additional file 4], we confirm that the jal mutation is recessive, and conclude that it must reside in an autosomal portion of the genome.
Complementation testing between jal and a targeted mutation in Il2ra
A recent genome-wide association study for alopecia areata (AA, OMIM #104000) in humans has implicated several genes, including IL-2RA (for interleukin 2 receptor, alpha chain) in the development of disfiguring hair loss . Because AA appears similar in at least some ways to the mutant jal/jal phenotype in mice , and because IL-2RA is located on human Chr 10p15.1—a region that is orthologous with the D2Mit359 and D2Mit80 interval on Chr 2 in mouse—we decided to test jal for complementation with the recessive Il2ra tm1Dw loss-of-function mouse mutation . Because mice homozygous for the targeted mutation show poor survival, we crossed Il2ra tm1Dw /+ heterozygous females with jal/jal males. If jal were a defect in Il2ra, then the mice that inherit jal and Il2ra tm1Dw could express no wild-type gene product, and would therefore be expected to show some mutant phenotype, perhaps as mild as defective vibrissae (as displayed by all jal/jal mutants) or perhaps as severe as the slower growth and progressive wasting (cachexia) seen in mice homozygous for Il2ra tm1Dw . Alternatively, if jal and Il2ra are distinct genes, then all of the progeny would be phenotypically normal (since both mutations are recessive).
This cross yielded 19 offspring that were typed by PCR for the Il2ra tm1Dw targeted disruption [Additional file 5] and observed for 30 weeks. DNA typing identified 11 Il2ra tm1Dw carriers (5 females and 6 males) and 8 mice without the targeted disruption (7 females and 1 male), not significantly different from the 1:1 ratio expected for a test cross (χ2 = 0.47; P = 0.49). All of these mice (Il2ra tm1Dw carriers and noncarriers) displayed normal vibrissae and body hair. Furthermore, Il2ra tm1Dw carriers and noncarriers showed indistinguishable growth rates (over a period of 30 weeks), with no signs of the cachexia seen in Il2ra tm1Dw /Il2ra tm1Dw controls [Additional file 6]. These data suggest that jal is not an allele of Il2ra.
Refinement of the meiotic map for jal
Evaluation of Gata3 as the possible genetic basis of the jalmutation
To determine if jal could be a mutant allele of the Gata3 gene, we imported a mouse carrying an engineered Gata3 null allele, Gata3 tm1Gsv , for complementation testing. To create litters of half experimental (doubly heterozygous) and half control offspring (carriers of the jal allele, only), we crossed Gata3 tm1Gsv /+ heterozygous females with jal/jal males. If jal is the result of a defect in Gata3, then the mice that inherit both jal and Gata3 tm1Gsv could express no wild-type gene product, and would therefore be expected to show defective coats and vibrissae. Alternatively, if jal and Gata3 are distinct genes, then the dihybrid progeny (jal/+, Gata3 tm1Gsv /+) would be phenotypically normal.
All coding regions of the Gata3 gene, plus the 5′ untranslated regions encoded by two alternative 1st exons (see Figure 4b for transcript diagram and summary) were sequenced in DNA isolated from C3H/HeJ and C3H/HeJ-jal/J mice. However, we found no differences in DNA sequence between these coisogenic wild type and mutant strains. In addition, using total RNA isolated from skin and from thymus, we amplified (and sequenced) only identically-spliced Gata3 cDNA from both wild type C3H/HeJ and C3H/HeJ-jal/J mutant mice (see Additional file 7).
The results presented suggest to us that the jal mutation is a mutant allele of the Gata3 gene on mouse Chr 2. We therefore recommend that the jal designation be changed to Gata3 jal . While we have not yet been able to pinpoint a sequence-level change in Gata3 jal , our analysis has mostly been limited to coding regions. We hypothesize that the Gata3 jal defect is likely to be a regulatory mutation (perhaps located in the promoters, introns, or 3′ untranslated region) that—in some fashion—impacts expression, processing, or degradation of the Gata3 jal transcript, although we find that the Gata3-001 transcript appears to be normally spliced. (We found no evidence for expression of the alternative Gata3-201 transcript in total RNA isolated from skin or thymus.) Quantitative and qualitative evaluation of Gata3 transcripts or protein in the epidermis and hair follicles of C3H/HeJ-jal mice versus wild type controls could help refine this array of possibilities. This prediction (that the Gata3 jal defect is likely to be a regulatory mutation) does seem consistent with the variable phenotypic presentation of focal alopecia that we observe in Gata3 jal /Gata3 jal mice (see Additional file 1). Since at least some patches of normal fur are seen on most if not all mutants (with some mutants showing almost entirely normal coats), we anticipate that a standard primary protein sequence (albeit improperly regulated) is likely to be encoded by the Gata3 jal allele.
The positional assignment of jal did not reveal (as with our introductory examples, refs. 1–9) an unsuspected function of Gata3 in skin, since the study of mouse strains engineered to carry targeted mutations have previously indicated a role for Gata3 in hair follicle development and skin cell lineage determination. Mice homozygous for germline Gata3 null mutations die around embryonic day 11 [22, 23], precluding a detailed assessment of the functional role of Gata3 in hair follicle morphogenesis. However, some investigators have rescued mutant skin by transplantation to athymic hosts , or else ablated Gata3 specifically in the epidermis and hair follicles to reveal a crucial role in skin . Since the mouse juvenile alopecia phenotype (patchy hair loss) is distinct from that of these conditionally-targeted mutants (complete baldness)—whatever its molecular basis—we believe that Gata3 jal likely offers a novel mutant allele, compared to the existing set of engineered Gata3 disruptions. Addition of this viable and phenotypically-unique natural variant to the Gata3 mutational inventory will surely allow new approaches to the functional analysis of this locus, just as the recent assignment of the spontaneous mouse frizzy (fr) and rat “hairless” (fr CR ) mutations to the prostasin gene  has productively advanced the in vivo analysis of Prss8 function in mammalian skin [27–29].
Haploinsufficiency of human GATA3 (due to loss-of-function mutation of GATA3) causes a dominantly-inherited syndrome of hypoparathyroidism, sensorineural deafness, and renal disease (HDR, OMIM #146255) also known as Barakat syndrome. Notably, HDR syndrome does not appear to involve immune-related disorders or alopecia [30, 31]. The mouse Gata3 tm1Gsv mutation has been shown to generate deafness in heterozygotes [32–34], and is considered a model for HDR. It would certainly be interesting to investigate parathyroid, cochlear, and renal function in Gata3 jal homozygotes and heterozygotes. In any case, a molecular explanation for the distinct modes of inheritance and phenotypic presentations of juvenile alopecia in mice versus HDR in humans will require discovery of the precise structure of the Gata3 jal allele.
Histological observation of immune cell infiltrates associated with follicular dystrophy in AA [35, 36] combined with Petukhova et al.’s linkage of genes involved in both innate and acquired immunity (including IL-2RA) to AA susceptibility  seem to firmly establish AA as an autoimmune disorder. Although Gata3 is known to play a crucial role in T cell development [22, 37], our elimination of Il2ra as the basis of the mutant phenotype as well as McElwee et al.’s failure to detect any signs of hair follicle inflammation in jal/jal mutants  suggest that mouse juvenile alopecia does not provide an ideal model for AA. However, it remains possible that juvenile alopecia could provide an animal model for at least some forms of focal alopecia which may have their primary defect in the hair follicle and lack an inflammatory component, but which may nonetheless be diagnosed as AA based on similar pathophysiology (i.e., patchy hair loss). Indeed, the future study of mouse juvenile alopecia may be helpful in identifying such a homologous human condition, defining approaches for distinguishing that disorder from AA, and in developing appropriate, specialized treatments.
The recessive jal mutation in mice maps to proximal Chr 2, and has been shown by complementation testing to be a variant allele of the Gata3 gene. While further study will be needed to discover the molecular defect in Gata3 that is the basis of the mutant phenotype, this spontaneous mouse variant promises to provide an animal model for some forms of focal alopecia in humans that have their primary defect in the hair follicle and lack an inflammatory component.
TRK is a professor in the Department of Biomolecular Sciences at Central Connecticut State University (New Britain, CT). FR was a student in the Master of Arts program in Biomolecular Sciences, and AMF, EBA, AS, NV-S, JMH, LAR, KMC, SRH and DVS were undergraduates majoring in Biomolecular Sciences or Biochemistry at CCSU when they conducted this research.
The authors thank CCSU undergraduates Randy Taylor, Adrian Pacheko, Anthony Ferrante, Nisrine Dagamseh, Amarilis Perez; and numerous high-school interns (including Edie Tinker, Mariam Hasan, Somaly Chhean, Rick Deschenes, Alicia Davis, Joshua Wrice, Marcelino Thillet, Ananda Thillet, Danerick Peralta, Diego Peralta, Ashley Feliciano, Krystal Garcia, Kayla Garcia, Jodalis Montalvo, Milagros Molina, Brianna Cirinna, and Rebecca Fuentes) for help with marker typing. We also thank Dr. James Douglas Engel (Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, MI, USA) for donation of mice carrying the Gata3 tm1Gsv null mutation, and Mary Mantzaris for excellent animal care. This work was supported by AREA grant 1R15AR059572 from the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS).
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