Waved with open eyelids 2 (woe2) is a novel spontaneous mouse mutation in the protein phosphatase 1, regulatory (inhibitor) subunit 13 like (Ppp1r13l)gene
© Toonen et al.; licensee BioMed Central Ltd. 2012
Received: 7 June 2012
Accepted: 24 July 2012
Published: 28 August 2012
Waved with open eyelids 2 (woe2) is a novel autosomal recessive mouse mutation that arose spontaneously in our animal facility. Upon initial evaluation, mutant mice exhibited eyelids open at birth (EOB) and wavy fur phenotypes. The goals of this study were to phenotypically characterize the woe2 mice and to identify the gene harboring the mutation responsible for the woe2 phenotype.
Histological analysis of woe2 embryos identified the failure of embryonic eyelid closure. Clinical and histological analysis of woe2 adult eyes identified severe corneal opacities, abnormalities of the anterior segment of the eye, and the absence of meibomian glands. Abnormalities in the fur texture and the absence of meibomian glands prompted us to evaluate other epidermal appendages: skin, teeth, and nails--as well as lacrimal, mammary, salivary, sebaceous and sweat glands. No obvious morphological differences between WT and woe2 mice were identified in these tissues. However, the analysis of woe2 identified cardiac abnormalities. Positional cloning of the woe2 locus identified a 1308 bp deletion in the Ppp1r13l gene. The deletion resulted in an aberrant Ppp1r13l Δexon9-11 transcript that lacks exons 9, 10 and 11 resulting in a premature stop and a loss of 223 amino acids from the C-terminal end of the putative mutant PPP1R13L protein. Immunohistological analysis during eye development identified expression of PPP1R13L in the palpebral epidermis, palpebral and bulbar conjunctiva, corneal epithelium and meibomian glands.
The woe2 mouse harbors a novel deletion within the Ppp1r13l gene, likely resulting in a complete loss of PPP1R13L function. Results from this study provide evidence that PPP1R13L has an essential role in embryonic eyelid closure as well in development of meibomian glands and the anterior segment of the eye. The woe2 mice are a useful model for investigation of the role of PPP1R13L, especially during ocular and eyelid development.
KeywordsEOB Eyelid Embryonic Meibomian Mapping Microsatellite Locus Mutation Deletion
As a part of mammalian ocular development the eyelids form, grow over the cornea, meet, and temporarily fuse . The closed eyelids serve as a protective barrier preventing premature exposure of developing ocular structures to the environment. Once conjunctival and corneal epithelia reach their maturity, the eyelid junction begins to break down and the eyelids reopen . Whether different mammalian species are born with the eyelids open or closed is determined by the stage of the ocular development specific for the species at the time of birth . In mice, eyelid formation is initiated at embryonic day 11.5 (E11.5) by invagination of the dorsal and ventral periocular ectoderm resulting in the formation of the primitive eyelid [1, 3]. By E15.5, the leading edges of the eyelid form at the tip of the primitive eyelids and start to migrate towards each other. By E16.5, the eyelids meet and form a junction and by E17 embryonic eyelid closure is fully completed [1, 3]. Mice are born with their eyelids closed and they remain closed until postnatal days 10 to 12 (P10-12) at which time they reopen . When eyelids fail to close properly before birth, the result is often severe corneal inflammation, defects in the anterior segment and blindness [3, 4]. Forward and reverse genetic approaches have identified genes essential for embryonic eyelid closure that, when mutated, lead to the “eyelids-open-at-birth” (EOB) phenotype. Given that mice are born with their eyelids closed, the EOB phenotype is easily identified by observation of the eyelids of newborn pups. EOB phenotypes have been identified to be associated with many genotypes; in fact, Mouse Genome Informatics (MGI) (http://www.informatics.jax.org/) lists 138 genotypes associated with the EOB phenotype indicating numerous genes and molecular pathways associated with this process.
A subgroup of mutant mice with the EOB phenotype also exhibit wavy fur. Molecular and genetic analyses showed that the majority of the mice with EOB and wavy fur phenotypes have defects in epidermal growth factor receptor (EGFR) signaling. Specifically, mice with mutations in the transforming growth factor alpha (Tgfa) [5, 6], a disintegrin and metallopeptidase domain 17 (Adam17) [7–9] and Egfr which encodes the EGFR receptor [10–14] all exhibit EOB and wavy fur phenotypes. EGFR signaling plays an essential role in regulating the eyelid leading edge migration through activation of the EGFR-ERK signaling cascade . Interestingly, another mouse mutant termed waved 3 (wa3) also exhibits the EOB and wavy fur phenotypes similar to those observed in mice with EGFR signaling defects . The wa3 mice have a mutation in Ppp1r13l , a gene that belongs to the Apoptosis Stimulating Proteins of p53 (ASPP) family of proteins. Although PPP1R13L is a highly conserved protein from C. elegans to human  the role of PPP1R13L remains poorly understood. It has been shown that PPP1R13L acts as a regulator of p53-mediated apoptosis  and as a regulator of the NF-кB subunit p65-RelA gene expression . Recently, it was also shown that PPP1R13L, via its regulation of p63, is a key regulator of epithelial homeostasis  and epithelial stratification .
Here we report a novel autosomal recessive mouse mutation that arose spontaneously in our mouse colony. Initial observations showed that the mutant mice exhibit EOB and wavy fur phenotypes. The identified phenotypes observed in the mutant mice resemble those in waved with open eyelids (woe) mice carrying a hypermorphic mutation in Adam17, previously studied in our lab . Thus, we termed the newly identified mutant mice waved with open eyelids 2 (woe2). A detailed examination of woe2 phenotypes revealed that a defect in embryonic eyelid closure is responsible for the woe2 EOB phenotype observed at birth. Additional ocular phenotypes in woe2 mice include severe corneal opacities, defects in the structures of the anterior segment of the eye, and the absence of the meibomian glands. In addition to ocular and wavy fur phenotypes, woe2 mice also exhibited severe cardiac defects. Genetic analysis showed that the woe2 phenotypes are due to a 1308 bp deletion in the Pppr13l gene. The identified deletion results in aberrantly spliced Ppp1r13l transcript and a putative truncated PPP1R13L protein lacking C-terminal functional domains. These findings uncover previously unidentified roles for PPP1R13L during eyelid and ocular development.
The woe2 mutation arose spontaneously on a mixed C57BL/6X129/SvJ background. The woe2 locus was maintained by brother-sister breedings. The C3A.BLiA-Pde6b+/J strain, which is a Pde6b(+) strain of C3H/HeJ (http://jaxmice.jax.org/strain/001912.html), and C57BL/6J were obtained from the Jackson Laboratory (Bar Harbor, ME). All strains exhibited normal breeding patterns and litter sizes. The treatment and use of all animals in this study was compliant with all protocols and provisions approved by the Institutional Animal Care and Use Committee (IACUC) at the Medical College of Wisconsin.
Clinical evaluation, histology and electron microscopy
For clinical analysis, mouse eyes were examined with a Topcon SL-D8Z slit lamp biomicroscope, following mydriasis with 1% Atropine Sulfate (Bausch & Lomb). The eyes were imaged with a Nikon SLR-based Photo Slit Lamp imaging system as previously described . For tissue analysis, E0.5 was defined as the morning of the day that a vaginal plug was first observed in a female. Embryonic and postnatal tissues were collected and fixed in either Zinc-formalin, Davidson’s solution, or 4% paraformaldehyde, then embedded in paraffin and sectioned to 4 μm thickness and stained with H&E using standard procedures as previously described . For scanning electron microscopy (SEM), E15.5 and E16.5 wild-type and woe2 embryo heads were collected, fixed in 2% glutaraldehyde in 0.1 M sodium cacodylate buffer, rinsed in buffer and dehydrated in ethanol. The samples were then critical-point dried in a Bal-tec CPD050, gold sputter coated in a Denton Desk II and viewed in a FEI XL30 SEM.
Antigen retrieval was performed in 1x citrate Buffer (Invitrogen) warmed to 95°C for 20 minutes. Sections were allowed to cool to room temperature and subsequently blocked in 10% normal goat serum with 1% bovine serum albumin in PBS for one hour. Slides were incubated at 4°C for one hour with monoclonal anti- PPP1R13L primary antibody (Sigma-Aldrich) at 1:200. Slides were then washed 3x in PBST and incubated for 20 minutes with goatαmouse Alexa633 (Invitrogen) secondary antibody at 1:1000. Slides were washed 3x in PBST and mounted with Vectashield mounting medium containing DAPI (Vector Labs).
The woe2 homozygote mice were outcrossed to C3A.BliA-Pde6β+/J; the resulting F1 progeny were backcrossed which generated 164 F2 progeny. These progeny were evaluated at three weeks of age for the presence of the wavy fur and were clinically evaluated for ocular abnormalities. Following phenotyping, the F2 progeny were euthanized and tissues were collected. Genomic DNA was purified from collected tissues as previously described . Initially, 25 F2 progeny were genotyped as previously described  with polymorphic microsatellites from Chr. 6: D6Mit188, D6Mit320, D6Mit323; Chr. 7: D7Mit340, D7Mit160, D7Mit148; Chr. 11: D11Mit19, D11Mit229, D11Mit294; Chr. 12: D12Mit12, D12Mit147, D12Mit52. For fine mapping on chromosome 7 all 164 progeny were genotyped with D7Mit1, D7Mit22, D7Mit224, D7Mit340, D7Mit160, and D7Mit148. Linkage was determined using Map Manager QTX software (http://www.mapmanager.org).
Sequence analysis of Ppp1r13l
For exonic and intron/exon junction genomic sequence analysis, primers were designed to anneal 50 bp upstream and downstream from intron/exon junctions. PCR products were amplified and sequenced as previously described . For cDNA analysis, RT-PCR was performed using total RNA from wild-type, woe2/+, and woe2/woe2 tissues, utilizing hearts, spleens, or eyes as previously described . The list of primer sequences is summarized in Additional file 1: Table S1. Long range PCR was conducted using the GeneAmp XL PCR kit (Roche, Branchburg, NJ) with primers (5’ CTGTCCACAATTACAGAGGGATCTGAA G3’) and (5’ CGGAAAGACAGCTCATCCCCAAACTCT 3’) as previously described . DNAStar software was utilized for comparative analysis of the sequences.
Positional cloning of woe2
Genomic sequence analysis of Ppp1r13l exons 1–8 and exon 12 including intron/exon junctions did not identify any difference between the Ppp1r13l reference sequence (NC_000073.5) and sequences from woe2. Although conventional PCR produced PCR products for exons 9, 10, and 11 when using genomic DNA from WT animals, it did not produce any PCR products when using genomic DNA from woe2 animals. This suggested a possible genomic rearrangement across the Ppp1r13l exon 9-11 region in the woe2 animals. Long range-PCR from exon 8 to exon 12 and subsequent sequencing revealed a 1308 bp deletion in woe2 (Figure 4B). The deletion break points were identified in Ppp1r13l intron 8 at −271 bp upstream from the 5' end of exon 9 and in intron 11 at −1203 bp upstream from the 5' end of exon 12 (Figure 4B).
To determine the molecular consequences of the 1308 bp deletion on the splicing of the Ppp1r13l transcript in the woe2 tissues, we proceeded to evaluate Ppp1r13l cDNA. RT-PCR analysis from woe2 tissues identified a single Ppp1r13l transcript that exhibited aberrant splicing from exon 8 to exon 12 with exons 9, 10 and 11 missing (Figure 4D). RT-PCR analysis of Ppp1r13l from WT tissues identified a transcript that matched the Ppp1r13l reference sequence (NM_001010836.3) (Figure 4C). The aberrant Ppp1r13l Δexon9-11 transcript identified in woe2 encodes a putative PPP1R13L mutant protein with a frame shift following M601, an addition of 7 amino acids (TWNKAWD), and a premature stop. The putative mutant PPP1R13L lacks 223 amino acids from the C-terminal end (Figure 4E).
The woe2EOB phenotype
PPP1R13L expression in the developing eyelids
In this study we characterized woe2, a novel mouse mutation which arose spontaneously. Genetic analysis of the woe2 locus identified a 1308 bp deletion in the Ppp1r13l gene encompassing exons 9 through 11 resulting in an aberrant Ppp1r13l Δexon9-11 transcript. The putative woe2 PPP1R13L protein encoded by the Ppp1r13l Δexon9-11 transcript lacks 223 amino acids from the C-terminal end. PPP1R13L, at the C-terminal end, is characterized with ankyrin (AKN) repeats, and a SRC homology (SH3) domain . The biochemical analyses of PPP1R13L have established that the ANK repeats and the SH3 domain are essential for the PPP1R13L binding with its partners: p53 , p65RelA , and p63 . The 223 amino acids missing from the mutant PPP1R13L from woe2 encompass both the ANK repeats and the SH3 domain. Although we did not functionally evaluate the truncated woe2 PPP1R13L protein, we expect that a loss of 223 amino acids may compromise the stability of the mutant woe2 PPP1R13L protein. Even if the mutant woe2 PPP1R13L protein remains s, the loss of the ANK repeats and the SH3 domain most likely would result in a complete loss of PPP1R13L function. This is consistent with the findings previously reported for wa3 mice that carry a 14-bp deletion in Ppp1r13l resulting in a loss of the SH3-domain from the C-terminal end . The mutant PPP1R13L protein from wa3 mice exhibited a loss of binding to the p65RelA subunit of NF-кB , a previously established PPP1R13L binding partner . As such, wa3 was established as a Ppp1r13l loss-of-function mutation . These findings collectively suggest that woe2 is a novel Ppp1r13l loss-of-function mutation.
The wavy fur and cardiac phenotypes identified in woe2 resemble the cardiac and wavy fur phenotypes previously characterized in the wa3 mice . Abnormalities in the fur and heart were also reported for cattle affected with cardiomyopathy and wooly hair coats (CWH) syndrome that carry a frame-shift mutation in the bovine ortholog of the Ppp1r13l gene . Although the EOB phenotype was also reported for wa3 mice, it was not further investigated . As a part of this study we established that in woe2 the EOB phenotype is due to a defect in embryonic eyelid closure. Even though the morphological analysis of woe2 embryonic eyelids did not identify any obvious abnormalities in the formation of the primitive eyelid, the formation of the leading edge or accumulation of peridermal cells at the leading edge, the woe2 embryonic eyelids failed to close. Immunohistochemical analysis showed that PPP1R13L was expressed in the eyelid epithelial sheet including epidermis, palpebral and bulbar conjunctiva, as well as in the cells of the leading edge. It has been shown before that the embryonic eyelid closure process depends on the movements of the epithelial sheet of the developing eyelids in a morphogenic process similar to dorsal closure in Drosophila . In the developing epidermis of the skin, via its interaction with p63, PPP1R13L regulates the expression of genes that play an essential role in cell-matrix adhesion, as well as in epithelial cell junctions . In addition, PPP1R13L was identified to regulate cell senescence and is required for epithelial stratification . Given that the role of PPP1R13L during embryonic eyelid closure has never been investigated, our current hypothesis is that PPP1R13L interacts with p63 in a similar way as it does in the developing epidermis of the skin and regulates the expression of the adhesion genes and/or genes involved in the differentiation of the cells of the leading edge. Our hypothesis is further supported by the observation that p63 −/− mice also exhibit the EOB phenotype even though the development of the eyelids proceeds normally prior to the embryonic eyelid closure . Although our current hypothesis implicates a role of PPP1R13L via interactions with p63, we cannot exclude the possibility that PPP1R13L may also be involved in molecular processes via interactions with the two other partners p65RelA and/or p53. Therefore, the role of PPP1R13L, as well as which molecular pathways are affected during embryonic eyelid closure requires further investigation.
Results from this study also identified the absence of meibomian glands in the woe2 eyelids. Meibomian glands along with hair, teeth, nails and exocrine glands are epidermal appendages formed from an ectodermal placode . Ectodermal dysplasia syndromes comprise a group of greater than 175 highly diverse disorders characterized by abnormalities of at least two ectodermal tissues where at least one involves hair, teeth, nails or sweat glands. In ectodermal dysplasia patients, other structures exhibiting abnormalities may include the mammary glands, thyroid gland, thymus, anterior pituitary, adrenal medulla, central nervous system, external ear, melanocytes, cornea, conjunctiva, lacrimal gland and lacrimal duct and meibomian glands . Interestingly, alterations of or the absence of meibomian glands was identified as one of the most reliable clinical ocular indications in ectodermal dysplasia patients . In addition to the absence of meibomian glands, evaluation of woe2 eyes revealed abnormalities of the cornea and the anterior structures. The corneal epithelium is a tissue also originating from the surface ectoderm ; proper maturation of the corneal epithelium plays an essential role in ocular development, especially for the development of the anterior segment . Taken together, these findings, along with the structural hair abnormalities previously identified as responsible for the wavy fur in wa3 mice , prompted us to morphologically evaluate other epidermal appendages in woe2 mice. However, our analysis did not identify any obvious defects in teeth, nails, lacrimal, salivary, mammary, sebaceous and sweat glands in woe2 mice. Our results suggest that PPP1R13L may have unique roles in the development of meibomian glands, cornea and hair follicles although PPP1R13L may have overlapping roles in the development of other ectodermal appendages.
It should be noted that the abnormalities in the cornea and anterior segment structures identified in woe2 mice may be solely related to the premature exposure to the environment consequent to the failure of the embryonic eyelid closure. Furthermore, the absence of meibomian glands may be further contributing to the abnormalities of the cornea--especially the corneal epithelium. Meibomian glands produce a lipid-rich secretion called meibum that is released from the orifices of the glands; the meibum is spread across the ocular surface and mix with tears produced by lacrimal glands to produce tear film that covers the entire ocular surface and has a protective, lubricatory, nutritional, and antimicrobial roles . A dysfunction of meibomian glands results in abnormalities of the tear film and consequently ocular irritation, inflammation and ocular surface disease . At this point, the molecular etiology of the anterior segment defects in woe2 remains unclear. It should be also noted that woe2 EOB and ocular phenotypes reported in this study are very similar to phenotypes reported for mice with defects in EGFR signaling pathway [5–14]. While no functional relationship between PPP1R13L and EGFR signaling has been reported, the similarities in the eyelid and ocular phenotypes as well as hair phenotypes identified in woe2 and mice with EGFR signaling defects suggest a common molecular pathway. Taken together, woe2 mice provide an excellent resource for determining the role of PPP1R13L especially during development as well as for elucidating the molecular mechanisms associated with PPP1R13L function.
The woe2 mouse is a novel spontaneous autosomal recessive mutation exhibiting EOB and wavy fur phenotypes. Genetic analysis identified a deletion in the Ppp1r13l gene. A detailed morphological evaluation showed that EOB in woe2 mice is due to a defect in embryonic eyelid closure. In addition to EOB, woe2 mice exhibited defects in the eye anterior segment development and the absence of meibomian glands. The precise role of PPP1R13L during the embryonic eyelid closure, development of meibomian glands and anterior segment structures requires further investigation. We anticipate that woe2 mice will provide a useful model in elucidating the etiology and underlying mechanisms of PPP1R13L function.
We thank Dr. Joseph Besharse at the Medical College of Wisconsin for generously providing us with woe2 mice used in this study. We also thank Mr. Joseph Fogerty at the Medical College of Wisconsin for his help in preliminary studies. We would like to thank Mr. Doug Holmyard at the Mount Sinai Hospital, Toronto, Canada for his assistance with scanning electron microscopy. This work was supported in part by the National Institutes of Health grants EY18872 (D.J.S) and EY02414 (J.C.B.).
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