Blephar-ophimosis, Ptosis, and Epi-canthus inversus Syndrome (BPES) is an autosomal dominant genetic disorder characterized by craniofacial defects that mainly affect the development of the eyelids. There are two types of BPES: Type I consists of the four major features of blepharophimosis, ptosis, epicanthus inversus, and telecanthus plus premature ovarian failure (POF), leading to infertility in woman. Type II consists of only the eyelid malformations without gender preference. People with BPES are at an increased risk of developing vision problems such as nearsightedness (myopia) or farsightedness (hyperopia). They may also have eyes that do not point in the same direction (strabismus) and lazy eye (amblyopia) affecting one or both eyes. Mutations in the transcription factor forkhead box L2 (FOXL2) structure gene cause 70 percent of BPES. The FOXL2 gene provides instructions for making a protein that is involved in the development of the eyelids and the ovaries before birth. Approximately 30 percent of people with BPES do not have an identified FOXL2 structure gene mutation;the cause of the condition in these people is unknown but FOXL2 gene regulation maybe altered. Herein, we have investigated the effects of Notch1 signaling activation in peri-ocular mesenchymal cells (POMC) which contribute to the formation of the lid-specific structures including levator M?ellersmooth muscle, tarsus, and meibomian glands. Notch1 intracellular domain (N1-ICD) was conditionally mis-expressed in POMC (here refer to as POMCN1-ICD) of a novel triple transgenic mouse strain, namely Kera-rtTA/tetO-Cre/R26floxedN1-ICD (KR/TC/R26fN1- ICD), by pulse induction of doxycycline (Dox) at different developmental stages. These triple KR/TC/R26fN1-ICD mice exhibited variegation of eyelid anomalies resembling BPES in humans. Our preliminary data showed that N1-ICD expression caused specific reduction of FoxL2 and smooth muscle differentiation marker gene, alpha-smooth actin (a-SMA) expressions in POMCs during eyelid morphogenesis. Our preliminary studies allow us to propose the hypotheses that sustained Notch signaling disturbs the formation of levator M?eller smooth muscle responsible for eyelid opening by down-regulation of FoxL2 in the POMC cells. In this application, we will further characterize KR/TC/R26fN1-ICD triple transgenic mouse as a novel animal model to study the pathogenesis of congenital BPES (Aim1). We will also delineate a molecular pathway that leads to the down-regulation of FoxL2 and subsequent malformation of the levator M?ellersmooth muscle during embryonic eyelid development (Aim2).
The goal of the proposed research is to understand the normal eyelid morphogenesis and the pathogenesis of human congenital blephrophimosis syndrome (BPES). Specifically, we plan to use transgenic mice and cell cultures to investigate the mechanism of how the Notch1 activation may serve as the upstream control of expression of FoxL2 by periocular mesenchyma, which are destined for M?eller smooth muscle development of the eyelids. Furthermore, the new knowledge will help us unravel signaling mechanisms of the Notch pathway in regulating FoxL2 gene expression governing levator M?eller smooth muscle differentiation during eyelid morphogenesis.
|Zhang, Lingling; Anderson, Matthew C; Liu, Chia-Yang (2017) The role of corneal stroma: A potential nutritional source for the cornea. J Nat Sci 3:|
|Zhang, Yujin; Wang, Yen-Chiao; Yuka, Okada et al. (2016) Mouse Corneal Stroma Fibroblast Primary Cell Culture. Bio Protoc 6:|
|Liu, Chia-Yang (2015) Wakayama symposium: role of canonical Notch signaling in conjucntival goblet cell differentiation and dry eye syndrome. BMC Ophthalmol 15 Suppl 1:152|
|Zhang, Yujin; Yeh, Lung-Kun; Zhang, Suohui et al. (2015) Wnt/?-catenin signaling modulates corneal epithelium stratification via inhibition of Bmp4 during mouse development. Development 142:3383-93|
|Dong, Fei; Liu, Chia-Yang; Yuan, Yong et al. (2015) Perturbed meibomian gland and tarsal plate morphogenesis by excess TGF? in eyelid stroma. Dev Biol 406:147-57|
|McCauley, Heather A; Liu, Chia-Yang; Attia, Aria C et al. (2014) TGF? signaling inhibits goblet cell differentiation via SPDEF in conjunctival epithelium. Development 141:4628-39|
|Ng, Gracia Y; Yeh, Lung-Kun; Zhang, Yujin et al. (2013) Role of SH2-containing tyrosine phosphatase Shp2 in mouse corneal epithelial stratification. Invest Ophthalmol Vis Sci 54:7933-42|
|Zhang, Yujin; Lam, Oliver; Nguyen, Minh-Thanh T et al. (2013) Mastermind-like transcriptional co-activator-mediated Notch signaling is indispensable for maintaining conjunctival epithelial identity. Development 140:594-605|
|Yuan, Yong; Call, Mindy K; Yuan, Yan et al. (2013) Dexamethasone induces cross-linked actin networks in trabecular meshwork cells through noncanonical wnt signaling. Invest Ophthalmol Vis Sci 54:6502-9|
|Yuan, Yong; Yeh, Lung-Kun; Liu, Hongshan et al. (2013) Targeted overexpression of TGF-? in the corneal epithelium of adult transgenic mice induces changes in anterior segment morphology and activates noncanonical Wnt signaling. Invest Ophthalmol Vis Sci 54:1829-37|
Showing the most recent 10 out of 11 publications