Biology subjects

Lathrop, K.

Publications and source records attributed to Lathrop, K..

3 recordsLinked to original sources

bioRxiv2025

Characterization of zebrafish nucleus pulposus in development and aging: A fish model for probing human intervertebral disc degeneration and regeneration

Intervertebral disc (IVD) degeneration (IDD) contributes to low back and neck pain. The nucleus pulposus (NP) of the IVD is usually degenerated first in age-related IDD. Addressing NP degeneration remains challenging due to insufficient understanding of its etiologies. Here, we characterize zebrafish IVD, particularly the NP, and note several characteristics that are common to or different from those of mammals. The adult zebrafish NP can be partitioned into three sections: the NP envelope with a monolayer of basal cells, the peripheral region with clustered vacuolated and non-vacuolated NP cells, and the central fibrotic region with low cellularity. With age, the percentage of vacuolated NP cells decreases, whereas that of non-vacuolated NP cells increases, as in mammals. However, a cluster of vacuolated cells persists in the NP periphery even in aged zebrafish. Notably, the ratio of the span of the fibrotic NP center to NP diameter remains largely constant at 50% regardless of age, suggesting that the zebrafish NP can better maintain its overall shape and structure, compared to mammalian NP. The fibrotic NP center and cell-populated NP periphery serve as internal controls to each other for studying NP maintenance and fibrosis. With external development, high fecundity, and great regenerative capabilities, zebrafish may be a unique NP model to complement mammalian models for studying how the NP degenerates and how the dormant capability of NP regeneration may be revitalized in humans.

developmental biology↗

bioRxiv2021

Retinal ganglion cell survival after severe optic nerve injury is modulated by crosstalk between JAK/STAT signaling and innate immune responses in the zebrafish retina

Visual information is transmitted from the eye to the brain along the optic nerve, a structure composed of retinal ganglion cell (RGC) axons. The optic nerve is highly vulnerable to damage in neurodegenerative diseases like glaucoma and there are currently no FDA-approved drugs or therapies to protect RGCs from death. Zebrafish possess remarkable neuroprotective and regenerative abilities and here, utilizing an optic nerve transection (ONT) injury and an RNA-seq-based approach, we identify genes and pathways active in RGCs that may modulate their survival. Through pharmacological perturbation, we demonstrate that JAK/STAT pathway activity is required for RGC survival after ONT. Furthermore, we show that immune responses directly contribute to RGC death after ONT; macrophages/microglia are recruited to the retina and blocking neuroinflammation or depleting these cells after ONT rescues survival of RGCs. Taken together, our results support a model in which pro-survival signals in RGCs, mediated by JAK/STAT signaling, counteract the activity of innate immune responses to modulate RGC vulnerability and resilience in the zebrafish retina after severe optic nerve damage.

neuroscience↗

bioRxiv2018

Regeneration of the zebrafish retinal pigment epithelium after widespread genetic ablation

The retinal pigment epithelium (RPE) is a specialized monolayer of pigmented cells within the eye that is critical for maintaining visual system function. Diseases affecting the RPE have dire consequences for vision, and the most prevalent of these is atrophic (dry) age-related macular degeneration (AMD), which is thought to result from RPE dysfunction and degeneration. An intriguing possibility for treating RPE degenerative diseases like atrophic AMD is the stimulation of endogenous RPE regeneration; however, very little is known about the mechanisms driving successful RPE regeneration in vivo. Here, we developed a zebrafish transgenic model (rpe65a:nfsB-GFP) that enabled ablation of large swathes of mature RPE. RPE ablation resulted in rapid RPE degeneration, as well as degeneration of Bruchs membrane and underlying photoreceptors. Using this model, we demonstrate for the first time that larval and adult zebrafish are capable of regenerating a functional RPE monolayer after RPE ablation. Regenerated RPE cells first appear at the periphery of the RPE, and regeneration proceeds in a peripheral-to-central fashion. RPE ablation elicits a robust proliferative response in the remaining RPE. Subsequently, proliferative cells move into the injury site and differentiate into RPE. BrdU pulse-chase analyses demonstrate that the regenerated RPE is likely derived from remaining peripheral RPE cells. Pharmacological inhibition of Wnt signaling significantly reduces cell proliferation in the RPE and delays overall RPE recovery. These data demonstrate that the zebrafish RPE possesses a robust capacity for regeneration and highlight a potential mechanism through which endogenous RPE regenerate in vivo.\n\nSIGNIFICANCE STATEMENTDiseases resulting in RPE degeneration are among the leading causes of blindness worldwide, and no therapy exists that can replace RPE or restore lost vision. One intriguing possibility is the development of therapies focused on stimulating endogenous RPE regeneration. For this to be possible, we must first gain a deeper understanding of the mechanisms underlying RPE regeneration. Here, we ablate mature RPE in zebrafish and demonstrate that zebrafish regenerate RPE after widespread injury. Injury-adjacent RPE proliferate and regenerate RPE, suggesting that they are the source of regenerated tissue. Finally, we demonstrate that Wnt signaling is required for RPE regeneration. These findings establish an in vivo model through which the molecular and cellular underpinnings of RPE regeneration can be further characterized.

developmental biology↗