Malformation of Tear Ducts Underlies the Epiphora and Precocious Eyelid Opening in<i>Prickle 1</i>Mutant Mice: Genetic Implications for Tear Duct Genesis

Ru, Jiali; Guo, Dianlei; Fan, Jiaying; Zhang, Jiao; Ju, Rong; Ouyang, Hong; Wei, Lai; Liu, Yizhi; Liu, Chunqiao

doi:10.1167/iovs.61.13.6

Cited by 10 publications

(5 citation statements)

References 53 publications

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“…The only reported genetically engineered mice with tear duct dysplasia are the Prickle1 gene knockouts. 27 , 35 Similar to the STDOB animals, Prickle1 mutant mice showed epiphora with white discharge ( Figs. 3 A, 3 B).…”

Section: Resultsmentioning

confidence: 63%

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Obstruction of the Tear Drainage Altered Lacrimal Gland Structure and Function

Xiao

Guo

Liu

et al. 2023

Invest. Ophthalmol. Vis. Sci.

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Purpose Orbital glands and drainage conduits are two distinct entities that constitute the lacrimal apparatus system, the malfunction of which leads to a range of ocular surface disorders. Despite the close functional relationship, how the two parts interact under pathophysiological conditions has not been directly tested. The study aims to investigate the lacrimal gland (LG) structural and functional changes upon the drainage system obstruction, thus, testing their function link. Methods Dacryocystectomy was performed in C57BL/6 mice to create a surgical model for tear duct (TD) obstruction (STDOB). Prickle1 mutant line with congenital nasolacrimal duct dysplasia serves as a genetic model for TD obstruction (GTDOB). Alterations of the LG and the ocular surface in tear duct obstruction mice were examined. Results STDOB and GTDOB mice showed similar ocular surface phenotypes, including epiphora, corneal epithelial defects, and conjunctival goblet cell abnormalities. At the molecular and cellular levels, aberrant secretory vesicle fusion of the LG acinar cells was observed with altered expression and localization of Rab3d, Vamp8, and Snap23, which function in membrane fusion. LG secretion was also altered in that lactoferrin, lipocalin2, and lysozyme expression were increased in both LG and tears. Furthermore, STDOB and GTDOB mice exhibited similar LG transcription profiles. Conclusions Physical obstruction of tear drainage in STDOB or GTDOB mice leads to LG dysfunction, suggesting a long-distance interaction between the tear drainage conduits and the LG. We propose that various components of the lacrimal apparatus should be considered an integral unit in diagnosing and treating ocular surface diseases.

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Section: Resultsmentioning

confidence: 63%

“…To prepare tear proteins, pilocarpine (300 µg/kg body weight) was subcutaneously injected to stimulate lacrimal gland secretion. 35 Tears were collected from the eyelid margin into Eppendorf tubes using a 0.5 µl micropipette 5 minutes after injection and stored at −80°C.…”

Section: Methodsmentioning

confidence: 99%

Obstruction of the Tear Drainage Altered Lacrimal Gland Structure and Function

Xiao

Guo

Liu

et al. 2023

Invest. Ophthalmol. Vis. Sci.

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“…The observed defective VE was characterized by the flattened outer surface on the Prickle1 b/b EBs (Figure 2H–J, N–P ), a polarity event probably related to vectorial BM deposition during tear duct development. 23 , 29 To further investigate whether BM was also altered in the Prickle1 mutant EBs, we examined the expression and localization of the principal components of the BM in the differentiated control and Prickle1 b/b mutant EBs at D3.…”

Section: Resultsmentioning

confidence: 99%

“…The observed defective VE was characterized by the flattened outer surface on the Prickle1 b/b EBs (Figure 2H-J, N-P), a polarity event probably related to vectorial BM deposition during tear duct development. 23,29 To further investigate whether BM was also altered in the 3Y). The expression of Laminin receptor genes Itgb4 and a6 are also similar (Figure 3Y).…”

Section: Prickle1 Is Required For Bm Basal Deposition and Columnar Sh...mentioning

confidence: 99%

Prickle1‐driven basement membrane deposition of the iPSC‐derived embryoid bodies is separable from the establishment of apicobasal polarity

Guo,

Liu,

Zhang

et al. 2024

Cell Proliferation

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Basement membrane (BM) component deposition is closely linked to the establishment of cell polarity. Previously, we showed that Prickle1 is crucial for BM deposition and cell polarity events in tear duct elongation. To gain a deeper understanding of the intimate relationship between BM formation and cell polarity, we generated induced pluripotent stem cells (iPSCs)‐derived embryoid bodies (EBs) with a basement membrane separating the visceral endoderm (VE) and inner EB cell mass. We found that Prickle1 was highly expressed in VE of the normal EBs, and the Prickle1 mutant EBs displayed severely impaired BM. Notably, the formation of the basement membrane appeared to rely on the proper microtubule network of the VE cells, which was disrupted in the Prickle1 mutant EBs. Moreover, disruption of vesicle trafficking in the VE hindered BM secretion. Furthermore, reintroducing Prickle1 in the mutant EBs completely rescued BM formation but not the apicobasal cell polarity of the VE. Our data, in conjunction with studies by others, highlight the conserved role of Prickle1 in directing the secretion of BM components of the VE cells during embryonic germ layer differentiation, even in the absence of established general polarity machinery. Our study introduces a novel system based on iPSCs‐derived EBs for investigating cellular and molecular events associated with cell polarity.

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“…For in situ hybridization, full-length Fz5 cDNA was PCRed from a pRK5 expression vector, with RNA polymerase binding sites T3 and T7 flanked for antisense and sense RNA probes, respectively. Tissue preparation and in situ hybridization followed the protocol described by Ru et al 38 …”

Section: Methodsmentioning

confidence: 99%

Single-Cell Characterization of the Frizzled 5 (Fz5) Mutant Mouse and Human Persistent Fetal Vasculature (PFV)

Chen

Peng

et al. 2023

Invest. Ophthalmol. Vis. Sci.

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Purpose Persistent fetal vasculature (PFV) is a pathological condition accounting for 4.8% of children's blindness in the United States. However, the PFV cell composition and pathogenetic mechanisms are poorly understood. This study aims to characterize PFV cell composition and associated molecular features and attempts to lay a foundation for further understanding the disease. Methods Immunohistochemistry was conducted to characterize cell types at the tissue level. Single-cell RNA sequencing (sc-RNAseq) was performed on the vitreous cells derived from normal and Fz5 mutant mice at two early postnatal ages and human PFV samples. Bioinformatic tools were used to cluster cells and analyze their molecular features and functions. Results The findings of this study are as follows: (1) a total of 10 defined and one undefined cell types were characterized in both the hyaloid vessel system and PFV by sc-RNAseq and immunohistochemistry; (2) neural crest-derived melanocytes, astrocytes, and fibroblasts were specifically retained in the mutant PFV; (3) Fz5 mutants were found to possess more vitreous cells at early postnatal age 3 but returned to similar levels as the wild type at postnatal age 6; (4) altered phagocytic and proliferation environments and cell-cell interactions were detected in the mutant vitreous; (5) the human PFV samples shared fibroblast, endothelial and macrophage cell types with the mouse, but having distinct immune cells including T cells, NK cells and Neutrophils; and last, (6) some neural crest features were also shared between certain mouse and human vitreous cell types. Conclusions We characterized PFV cell composition and associated molecular features in the Fz5 mutant mice and two human PFV samples. The excessively migrated vitreous cells, intrinsic molecular properties of these cells, phagocytic environment, and cell-cell interactions may together contribute to PFV pathogenesis. Human PFV shares certain cell types and molecular features with the mouse.

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Malformation of Tear Ducts Underlies the Epiphora and Precocious Eyelid Opening inPrickle 1Mutant Mice: Genetic Implications for Tear Duct Genesis

Cited by 10 publications

References 53 publications

Obstruction of the Tear Drainage Altered Lacrimal Gland Structure and Function

Obstruction of the Tear Drainage Altered Lacrimal Gland Structure and Function

Prickle1‐driven basement membrane deposition of the iPSC‐derived embryoid bodies is separable from the establishment of apicobasal polarity

Single-Cell Characterization of the Frizzled 5 (Fz5) Mutant Mouse and Human Persistent Fetal Vasculature (PFV)

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