AP-2β is required for formation of the murine trabecular meshwork and Schlemm's canal

Akula, Monica; Taiyab, Aftab; Deschamps, Paula; Yee, Shannin; Ball, Alexander K.; Williams, Trevor; West‐Mays, Judith A.

doi:10.1016/j.exer.2020.108042

Cited by 6 publications

(9 citation statements)

References 31 publications

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“…Several mouse models relevant to early onset developmental forms of glaucoma have been described (Akula et al, 2020;Chang et al, 2001;Chen and Gage, 2016;Ishibashi et al, 1999;Iwao et al, 2009;Kroeber et al, 2010;Labelle-Dumais et al, 2020;Lachke et al, 2011;Smith et al, 2000;Thomson et al, 2017;Tolman et al, 2021). Among them, many studies have focused on phenotypes of the anterior segment and there have been relatively few in depth studies of RGC damage.…”

Section: Discussionmentioning

confidence: 99%

Quantification and image-derived phenotyping of retinal ganglion cell nuclei in theneemouse model of congenital glaucoma

Heide

Meyer

Hedberg-Buenz

et al. 2021

Preprint

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The nee mouse model exhibits characteristic features of congenital glaucoma, a common cause of childhood blindness. The current study of nee mice had two components. First, the time course of neurodegeneration in nee retinal flat-mounts was studied over time using a retinal ganglion cell (RGC)-marker, BRN3A; a pan-nuclear marker, TO-PRO-3; and H&E staining. Based on segmentation of nuclei using ImageJ and RetFM-J, this analysis identified a rapid loss of BRN3A+ nuclei from 4–15 weeks of age, with the first statistically significant difference in average density compared to age-matched controls detected in 8-week-old cohorts (49% reduction in nee). Consistent with a model of glaucoma, no reductions in BRN3A– nuclei were detected, but the combined analysis indicated that some RGCs lost BRN3A marker expression prior to actual cell loss. These results have a practical application in the design of experiments using nee mice to study mechanisms or potential therapies for congenital glaucoma. The second component of the study pertains to a discovery-based analysis of the large amount of image data with 748,782 segmented retinal nuclei. Using the automatedly collected region of interest feature data captured by ImageJ, we tested whether RGC density of glaucomatous mice was significantly correlated to average nuclear area, perimeter, Feret diameter, or MinFeret diameter. These results pointed to two events influencing nuclear size. For variations in RGC density above approximately 3,000 nuclei/mm2 apparent spreading was observed, in which BRN3A– nuclei—regardless of genotype—became slightly larger as RGC density decreased. This same spreading occurred in BRN3A+ nuclei of wild-type mice. For variation in RGC density below 3,000 nuclei/mm2, which only occurred in glaucomatous nee mutants, BRN3A+ nuclei became smaller as disease was progressively severe. These observations have relevance to defining RGCs of relatively higher sensitivity to glaucomatous cell death and the nuclear dynamics occurring during their demise.

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Section: Discussionmentioning

confidence: 99%

Quantification and image-derived phenotyping of retinal ganglion cell nuclei in theneemouse model of congenital glaucoma

Heide

Meyer

Hedberg-Buenz

et al. 2021

Preprint

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“…Previously, our laboratory had created the AP‐2β NCC KO mouse model in which the Wnt1Cre mouse line was used to delete AP‐2β from the cranial neural crest (Akula et al., 2020). These mice showed defects in the TM required for aqueous outflow, which hinted at a cell‐autonomous role for AP‐2β in TM development.…”

Section: Discussionmentioning

confidence: 99%

“…IHC was performed as previously described (Akula et al., 2020). Primary antibodies included AP‐2β (1:50, Cell Signaling, 2509S, Danvers, MA), α‐smooth muscle actin (αSMA, 1:100, Sigma Aldrich, A2547, Oakville, ON), myocilin (1:200, FabGennix, MYO‐101AP, Frisco, TX), endomucin (1:100, eBioscience, 14‐5851‐82, San Diego, CA), Prox1 (1:100, Covance, 925201, Princeton, NJ), N‐cadherin (1:100, BD Transduction, 610920, San Jose, CA), and Brn3a (1:100, sc‐8429, Santa Cruz, CA) (Bassett et al., 2012; Martino et al., 2016; Robertson et al., 2013; Taiyab et al., 2021) (Table 1).…”

Section: Methodsmentioning

confidence: 99%

“…Therefore, we previously used the Wnt1Cre transgenic line to conditionally delete AP‐2β from cranial NCCs (AP‐2β NCC KOs), allowing such mutant mice to be followed into adulthood (Martino et al., 2016). The resulting mice showed anterior segment defects, including loss of the corneal endothelium, a peripheral to central iridocorneal adhesion, and absence of formation of a TM region (TMR) and SC, in addition to increased IOP and glaucomatous features (Akula et al., 2020; Martino et al., 2016). However, it was unclear whether the peripheral to central iridocorneal adhesion, or the lack of a TM and SC due to AP‐2β deletion contributed to the increased IOP and glaucomatous features.…”

Section: Introductionmentioning

confidence: 99%

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Deletion of transcription factor AP‐2β from the developing murine trabecular meshwork region leads to progressive glaucomatous changes

Taiyab

Akula

Dham

et al. 2021

J of Neuroscience Research

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Glaucoma is one of the leading causes of irreversible blindness and can result from abnormalities in anterior segment structures required for aqueous humor outflow, including the trabecular meshwork (TM) and Schlemm's canal (SC). Transcription factors such as AP‐2β play critical roles in anterior segment development. Here, we show that the Mgp‐Cre knock‐in (Mgp‐Cre.KI) mouse can be used to target the embryonic periocular mesenchyme giving rise to the TM and SC. Fate mapping of male and female mice indicates that AP‐2β loss causes a decrease in iridocorneal angle cells derived from Mgp‐Cre.KI‐expressing populations compared to controls. Moreover, histological analyses revealed peripheral iridocorneal adhesions in AP‐2β mutants that were accompanied by a decrease in expression of TM and SC markers, as observed using immunohistochemistry. In addition, rebound tonometry showed significantly higher intraocular pressure (IOP) that was correlated with a progressive significant loss of retinal ganglion cells, reduced retinal thickness, and reduced retinal function, as measured using an electroretinogram, in AP‐2β mutants compared with controls, reflecting pathology described in late‐stage glaucoma patients. Importantly, elevated IOP in AP‐2β mutants was significantly reduced by treatment with latanoprost, a prostaglandin analog that increases unconventional outflow. These findings demonstrate that AP‐2β is critical for TM and SC development, and that these mutant mice can serve as a model for understanding and treating progressive human primary angle‐closure glaucoma.

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“…6,10 The periocular mesenchyme gives rise to several structures of the eye, such as the corneal stroma and endothelium, ciliary body stroma and muscle, anterior iris stroma and drainage structures. 7,36 TFAP2B knockout in murine neural crest cells by targeting a floxed allele with a Wnt1-Cre transgene resulted in defects in the anterior segment of the eye, leading to an increase in intraocular pressure and glaucoma. 7 Moreover, AP-2β is expressed in the central nervous system during embryogenesis.…”

Section: Ap-2β In Embryogenesis Development and Cellular Differentiationmentioning

confidence: 99%

Transcription factor AP‐2beta in development, differentiation and tumorigenesis

Raap

Gierendt

Kreipe

et al. 2021

Intl Journal of Cancer

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To date, the AP-2 family of transcription factors comprises five members. Transcription factor AP-2beta (TFAP2B)/AP-2β was first described in 1995. Several studies indicate a critical role of AP-2β in the development of tissues and organs of ectodermal, neuroectodermal and also mesodermal origin. Germline mutation of TFAP2B is known to cause the Char syndrome, an autosomal dominant disorder characterized by facial dysmorphism, patent ductus arteriosus and anatomical abnormalities of the fifth digit. Furthermore, single-nucleotide polymorphisms in TFAP2B were linked to obesity and specific personality traits. In neoplasias, AP-2β was first described in alveolar rhabdomyosarcoma. Immunohistochemical staining of AP-2β is a recommended ancillary test for the histopathological diagnosis of this uncommon childhood malignancy. In neuroblastoma, AP-2β supports noradrenergic differentiation.Recently, the function of AP-2β in breast cancer (BC) has gained interest. AP-2β is associated with the lobular BC subtype. Moreover, AP-2β controls BC cell proliferation and has a prognostic impact in patients with BC. This review provides a comprehensive overview of the current knowledge about AP-2β and its function in organ development, differentiation and tumorigenesis.

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AP-2β is required for formation of the murine trabecular meshwork and Schlemm's canal

Cited by 6 publications

References 31 publications

Quantification and image-derived phenotyping of retinal ganglion cell nuclei in theneemouse model of congenital glaucoma

Quantification and image-derived phenotyping of retinal ganglion cell nuclei in theneemouse model of congenital glaucoma

Deletion of transcription factor AP‐2β from the developing murine trabecular meshwork region leads to progressive glaucomatous changes

Transcription factor AP‐2beta in development, differentiation and tumorigenesis

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