Brian A. Link, PhD

Brian A. Link, PhDProfessor

Medical College of Wisconsin
Department of Cell Biology, Neurobiology & Anatomy
8701 Watertown Plank Road
Milwaukee, WI 53226-0509

(414) 955-8072
(414) 955-6517 (fax)

PhD, Oregon Health Sciences University, 1997
Postdoctoral, Harvard University

Graduate Programs
Program in Cell and Developmental Biology
Program in Neuroscience

Research Area

Genetics and cell biology of ocular development and disease

There are two major projects under study in the Link Lab: (1) Mechanisms of vertebrate retinogenesis and (2) Complex gene interactions underlying glaucoma-phenotypes. For both projects, we primarily utilize zebrafish. For the developmental studies, zebrafish provide a genetically amenable system that also facilitates in vivo live cell imaging studies. For the glaucoma phenotypes modeling, we principally utilize genetics, and in particular, the ability to conduct forward genetic screens for genes that contribute to complex (multi-factorial) phenotypes.

Mechanisms of vertebrate retinogenesis
There are several interrelated and ongoing projects for this topic. Emphasis has been placed on identifying regulators of retinogenesis by analyzing zebrafish mutants that show disrupted retinal lamination (Figure 1).

This phenotype is analogous to the "rough-eye" phenotype of the Drosophila ommatidium which has been so critical in understanding the principles of signaling during development. Characterizations of zebrafish mutants have shed light on fundamental processes of retinogenesis including regulation and selection of cell cycle exit, post-mitotic cell migration, and the mechanisms of coordinated cellular differentiation. Additional emphasis in our lab is now being placed on studying the process of interkinetic nuclear migration and its relationships to neurogenesis. Interkinetic nuclear migration is the cellular behavior where neuroepithelia nuclei migrate in an apical-basal manner in phase with the cell cycle. The process is heterogeneous among the progenitors. Confocal time-lapse imaging with cell type specific GFP-based transgenes revealed that particular patterns of interkinetic nuclear migration influence which progenitor cells exit the cell cycle (Baye and Link, 2007; Del Bene et al, 2008) (Figure 2 and Movie 1).

Figure 1

Figure 2

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Movie 1. In vivo confocal time-lapse movie shows heterogeneity of interkinetic nuclear migration in retinal progenitors from 24 hpf. Images are composed of compressed z-stacks of H2A-GFP fluorescence overlaid with single mid-plane bright-field images. Apical and basal surfaces are outlined with dashed white lines in the first and last frame and an arrow indicates a cell undergoing mitosis at the apical surface. The movie plays at 6 frames per second covering 12 hr of development time (Baye and Link, 2007).

Specifically, neuroepithelia with deep basal nuclear migrations and shorter cell cycles are biased to produce neurons, rather than give rise to daughter cells that re-enter the cell cycle. The lab is currently exploring the signals and mechanisms underlying these relationships.

Mechanisms of vertebrate retinogenesis

Complex gene interactions underlying glaucoma-phenotypesComplex gene interactions underlying glaucoma-phenotypes
The overall goal of these studies is to understand the relationships between genes that contribute to glaucoma-phenotypes. The glaucomas are a heterogeneous group of ocular disorders characterized by retinal ganglion cell death, optic nerve damage and visual field loss. Elevated intraocular pressure is a principal risk factor for this neurodegenerative disease. The majority and perhaps all forms of glaucoma are complex – requiring the interaction of multiple genes. While several genes that contribute to glaucoma have been identified, many additional loci remain unknown. We are using zebrafish to identify and study genes which promote glaucoma-phenotypes (Figure 3).

In particular, we are focusing on the complex-gene interactions that promote retinal ganglion cell death in the context of elevated intraocular pressure. Additional projects are focused on genes that regulate the development of glaucoma-relevant ocular tissues, as such genes have previously been shown to impact glaucoma (Movie 2).

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Movie 2. In vivo confocal time-lapse movie showing migration of neural crest cells into the periocular region of the eye. These cells, along with head mesoderm, contribute to the structures of the anterior segment that regulate intraocular pressure. Cells were labeled with the foxd3:GFP transgene (Gilmour et al. Neuron 34:577-88, 2002)

Brian Link, PhD

Recent Publications

Medical College of Wisconsin
8701 Watertown Plank Road
Milwaukee, WI 53226
(414) 955-8296
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