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Our Research


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Our Research


 
 

Our lab studies the cellular and molecular mechanisms underlying tissue morphogenesis: the process by which a group of cells achieves its proper cellular organization and shape. Using the vertebrate eye as a model, we want to understand how the cells that comprise the vertebrate optic cup – neural retina, retinal pigmented epithelium, and lens – form the stereotyped structure that is critical for visual function. Developmental defects in eye morphogenesis represent a common cause of serious visual impairment in newborns.

Using confocal microscopy and a custom-built software suite for tracking cell behaviors in four dimensions, we have previously generated a map encompassing all cellular movements and divisions during zebrafish optic cup morphogenesis. We found that a complex set of cell movements, coordinated between different tissues, is responsible for shaping the eye. Using this unprecedented dataset as a reference point, our current studies focus on the molecular mechanisms underlying eye morphogenesis. Our studies make use of zebrafish molecular genetics, cell biology, and live imaging, and include the following projects:

 
 

Cell-matrix adhesion and cell polarity


We found that the extracellular matrix component laminin is required for eye morphogenesis: in laminin-α1 mutants, optic stalk constriction and optic vesicle invagination are impaired. In addition, establishment of apicobasal polarity is impaired. However, we still do not understand how disrupted polarity leads to this phenotype, how polarity is initially established, or the signaling pathway downstream of laminin.

Cell-matrix adhesion and cell polarity


We found that the extracellular matrix component laminin is required for eye morphogenesis: in laminin-α1 mutants, optic stalk constriction and optic vesicle invagination are impaired. In addition, establishment of apicobasal polarity is impaired. However, we still do not understand how disrupted polarity leads to this phenotype, how polarity is initially established, or the signaling pathway downstream of laminin.

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Developmental signaling pathways


While signaling pathways such as Shh and Wnt are known to play a role in patterning the optic vesicle, their role in morphogenesis itself is unknown. By performing 4-dimensional cell tracking on zebrafish mutants and morphants, we will quantitatively determine the contributions of different developmental signaling pathways to eye morphogenesis.

Developmental signaling pathways


While signaling pathways such as Shh and Wnt are known to play a role in patterning the optic vesicle, their role in morphogenesis itself is unknown. By performing 4-dimensional cell tracking on zebrafish mutants and morphants, we will quantitatively determine the contributions of different developmental signaling pathways to eye morphogenesis.

Cell motility


During eye morphogenesis, we find that retinal progenitors have unexpectedly motile behaviors despite their epithelial polarization. Such behaviors are frequently regulated by Rho-family small GTPases, and we will investigate the involvement of these signaling molecules in coordinating the motility of single cells and the morphogenesis of entire sheets if tissue.

Cell motility


During eye morphogenesis, we find that retinal progenitors have unexpectedly motile behaviors despite their epithelial polarization. Such behaviors are frequently regulated by Rho-family small GTPases, and we will investigate the involvement of these signaling molecules in coordinating the motility of single cells and the morphogenesis of entire sheets if tissue.

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New genes identified in eye morphogenesis


Our 4D analysis suggests that coordination of cell movements between tissues is critical for eye morphogenesis. In addition, in a forward genetic screen, Kristen isolated a mutant, O15, in which extremely tight adhesion between the optic vesicle and the overlying ectoderm impairs invagination of both the optic vesicle and lens. We are isolating the underlying mutation and will determine the nature of the tissue-tissue interactions regulated by O15.

New genes identified in eye morphogenesis


Our 4D analysis suggests that coordination of cell movements between tissues is critical for eye morphogenesis. In addition, in a forward genetic screen, Kristen isolated a mutant, O15, in which extremely tight adhesion between the optic vesicle and the overlying ectoderm impairs invagination of both the optic vesicle and lens. We are isolating the underlying mutation and will determine the nature of the tissue-tissue interactions regulated by O15.

Publications


Publications


Bryan CD, Chien CB, Kwan KM (2016) Loss of laminin alpha 1 results in multiple structural defects and divergent effects on adhesion during vertebrate optic cup morphogenesis. Developmental Biology, In Press 

Kwan KM (2014) Coming into focus: The role of extracellular matrix in vertebrate optic cup morphogenesis. Developmental Dynamics 243:1242-8

Kwan KM, Otsuna H, Kidokoro H, Carney KR, Saijoh Y, Chien CB (2012) A complex choreography of cell movements shapes the vertebrate eye. Development 139:359-72
 
Kwan KM (2010) 25 years on, Developmental Biology remains dynamic, competent, and instructive (book review). Developmental Dynamics 239:3506-7

Kwan KM, Fujimoto E, Grabher C, Mangum BD, Hardy ME, Campbell DS, Parant JM, Yost HJ, Kanki JP, Chien C-B (2007) The Tol2kit: a multisite-gateway based construction kit for Tol2 transposon transgenesis constructs. Developmental Dynamics 236:3088-99

Funding


Funding


NIH/NEI
Knights Templar Eye Foundation
March of Dimes Basil O’Connor Starter Scholar Award
University of Utah Research Foundation