Yoshimatsu's Group

The Yoshimatsu Group investigates the molecular and genetic basis of retinal development and degeneration, especially how a specialized region called the high-acuity area forms and why this area is particularly susceptible to degenerative disease, such as Age-related macular degeneration. Research is conducted in two labs both led by Dr Yoshimatsu: at Washington University in St Louis and at the BioRTC.

In humans, the high-acuity area, also called the fovea, is a small (~1.5 mm) central region of the retina that contains neural populations and circuitry distinct from the rest of the eye and is responsible for the rich detailed high acuity vision, which enables us to read, see pictures, and recognize faces. Disruption of foveal development or maintenance results in sever visual impairment. Understanding the molecular and genetic mechanisms underlying foveal development and degeneration is critical for identifying treatment targets. However, two fundamental challenges constrain progress in this field: a lack of experimentally tractable model system that possess a fovea and a lack of genetic information associated with foveal development and diseases.

Our research program addresses these challenges through two complementary approaches:

1. Comparative approaches across vertebrate species to identify model systems for studying the human fovea.

Common lab animals, such as mice and rats, are nocturnal and do not possess a fovea-like structure in their retina. Therefore, there is a strongneed for alternative model animals with foveal specializations. At Washington University in St Louis, the Yoshimatsu lab uses zebrafish as a model. This model system offers established genetic tools and this animals are highly amenable to experimental manipulation. Furthermore, our previous work demonstrated that the zebrafish retina contains a fovea-like high-acuity region that resembles many aspects of the human fovea, including cellular arrangements, circuitry and physiological properties. We are currently testing whether mutations in genes associated with human foveal diseases can recapitulate similar pathological phenotypes in zebrafish.

At the BioRTC, our research focus on Agama agama, a lizard species abundant in West Africa. Many lizard species possess a fovea, and some even two foveae in the retina. Despite this unique feature, lizards have rarely been used for eye research. We are currently characterizing the foveal structure of Agama during development using immunostaining and confocal imaging to determine the similarity between human and Agama foveal organization.

2. Human genetics to identify candidate causal genes for foveal diseases.

We collaborate with human genetics labs to identify genes associated with foveal disorders such as foveal hypoplasia and age-related macular degeneration (AMD). At the BioRTC, we focus on AMD. AMD is the leading cause of visual impairment in the elderly worldwide. However, its prevalence varies significantly between European and African ancestries. AMD is three times more common in European descent than African descent. In contrast, glaucoma, the second leading cause of visual impairment, occurs ~50% more frequently in Africans than Europeans. By integrating eye exams into the ongoing dementia research cohorts (see the Maina Group), we aim to (1) determine whether AMD risk variants found in European decent are also present in African populations and (2) identify genetic variations associated with glaucoma in African populations. Africa harbors the greatest human genetic diversity due to the evolutionary history of humans. In particular, sub-Saharan Africa, including Northern Nigeria, hosts some of the highest levels of genetic variations. Common and critical genetic variants for diseases are expected to be evolutionarily old and shared across broad populations. Therefore, our comparative human genetic approach can reveal shared susceptibility genes and biological pathways for AMD and glaucoma, while also identifying variants specific to African populations.

By integrating these two approaches, we can experimentally test the functions of candidate genes identified in human populations, uncovering fovea-related disease mechanisms and identify potential targets for therapeutic intervention.

Key Research Questions

Our research focuses on several fundamental questions:

• What molecular pathways define the location of the fovea and induce the foveal formation?
• What characteristics make the fovea vulnerable to degenerative diseases?
• What genes cause foveal development and degeneration diseases?
• Can we recapitulate human foveal diseases in model animals?

Research Approaches and Technologies

To address these questions, the Yoshimatsu Group combines:

• genome engineering in model animals
• confocal and advanced light microscopy
• volumetric electron microscopy for neural circuit reconstruction
• two-photon functional imaging of neural activity

Collaboration and Opportunities

The Yoshimatsu Group welcomes collaborations in areas including:

• visual system development
• neurodegeneration
• visual ecology
• evolutionary biology

Researchers interested in collaborative projects or visiting opportunities are encouraged to contact the group.