Biology subjects

Donahue, J.

Publications and source records attributed to Donahue, J..

6 recordsLinked to original sources

bioRxiv2026

TFE3 fusions drive expression of CD44 and SPP1 in Translocation Renal Cell Carcinoma

Xp11.2 translocation RCC [Xp11.2 tRCC]) is an underdiagnosed and aggressive subtype of RCC with few specific or targeted therapies. The transmembrane glycoprotein CD44 is an emerging target in many advanced malignancies, and with its ligand OPN (SPP1), is a crucial driver of cancer progression, stemness, metastasis, and immune suppression. Here we show that common TFE3-fusions [ including SFPQ-TFE3, PRCC-TFE3, ASPSCR1-TFE3, and NONO-TFE3] are associated with upregulated expression of CD44 and SPP1, as observed in multiple human and murine bulk transcriptomic studies and a murine tRCC snRNA-Seq dataset. CD44 and/or SPP1 protein expression were also upregulated in murine models of transgenic tRCC kidneys and urine specimens, patient-derived cell lines and human tRCC cases, by immunoblotting and/or IHC. Transient deletion of CD44 was associated with profound and specific suppression of tRCC cell line growth, with decreased mTOR signaling. These data suggest that CD44 and/or SPP1 may potentially drive tumorigenesis in tRCC.

cancer biology↗

bioRxiv2024

Adult caudal fin shape is imprinted in the embryonic fin fold

Appendage shape is formed during development (and re-formed during regeneration) according to spatial and temporal cues that orchestrate local cellular morphogenesis. The caudal fin is the primary appendage used for propulsion in most fish species, and exhibits a range of distinct morphologies adapted for different swimming strategies, however the molecular mechanisms responsible for generating these diverse shapes remain mostly unknown. In zebrafish, caudal fins display a forked shape, with longer supportive bony rays at the periphery and shortest rays at the center. Here, we show that a premature, transient pulse of sonic hedgehog a (shha) overexpression during late embryonic development results in excess proliferation and growth of the central rays, causing the adult caudal fin to grow into a triangular, truncate shape. Both global and regional ectopic shha overexpression are sufficient to alter fin shape, and forked shape may be rescued by subsequent treatment with an antagonist of the canonical Shh pathway. The induced truncate fins show a decreased fin ray number and fail to form the hypural diastema that normally separates the dorsal and ventral fin lobes. While forked fins regenerate their original forked morphology, truncate fins regenerate truncate, suggesting that positional memory of the fin rays can be permanently altered by a transient treatment during embryogenesis. Ray finned fish have evolved a wide spectrum of caudal fin morphologies, ranging from truncate to forked, and the current work offers insights into the developmental mechanisms that may underlie this shape diversity.

developmental biology↗

bioRxiv2022

Static Stability and Swim Bladder Volume in the Bluegill Sunfish (Lepomis macrochirus)

The static stability of a fish in the water is determined by the relative locations of its center of mass and center of buoyancy. These locations may not be constant, but may depend on the volume of the swim bladder. Changes in swim bladder volume affect both the distribution of mass and the overall volume of the fish, thus affecting the location of the center of mass and center of buoyancy, respectively. To determine the static stability and to examine the influence of the swim bladder on static stability, we used micro-computed tomography to estimate the locations of the center of mass and center of buoyancy in bluegill sunfish (Lepomis macrochrius). In fish oriented head up in the scanner, we found that the center of buoyancy is located 0.441 body lengths from the snout and 0.19 body lengths above the ventral surface of the pelvic girdle, and that the center of mass is 0.0012 BL posterior to and 0.00045 BL ventral to the center of buoyancy. Swim bladders from our specimens ranged in size from 1.9% to 7.6% total body volume, and we found no correlation between swim bladder volume and the distance between the center of mass and center of buoyancy. However, in fish scanned in a head-down orientation, the center of mass is anterior and dorsal to the center of buoyancy--the opposite configuration of that found in fish oriented head up. This change in center of mass and center of buoyancy seems to be caused by changes in the location of the swim bladder in the body: the centroid of the swim bladder is located more posteriorly in fish oriented head-down. The air in the bladder "rises" while heavier tissues "sink," driving a change in tissue distribution and changing the location of the center of mass relative to the center of buoyancy. We conclude that while static stability does not change with swim bladder volume, pitch angle could have a marked effect on static stability.

biophysics↗

bioRxiv2022

Translational approach to increase phosphate accumulation in two plant species through perturbance of inositol pyrophosphates

Inorganic phosphate (Pi), while indispensable for all biological organisms and a major agricultural macronutrient, is an increasingly limited and nonrenewable resource. Recent studies demonstrate the importance of inositol pyrophosphates (PP-InsPs) in plant Pi signaling and homeostasis, however the extent to which PP-InsPs impact plant development is not well understood. We report that transgenic expression of the Saccharomyces cerevisiae enzyme Diadenosine and Diphosphoinositol Polyphosphate Phosphohydrolase (DDP1) in Arabidopsis thaliana and Thlaspi arvense (pennycress) provide a unique translational utility for Pi phytoremediation as well as unique germplasm and insight on the long-term impacts of reduced PP-InsPs. Transgenic DDP1 expression in Arabidopsis decreased PP-InsPs, impacted growth and development, and increased Pi accumulation leading to Pi toxicity. Analysis of Pi Starvation Response (PSR) marker genes indicated that the PSR is activated in DDP1 expressing plants. We assessed translational utility through transformation of pennycress, a spring annual cover crop with emerging importance as a biofuel crop, with a DDP1 transgene. Pennycress plants expressing DDP1 showed similar altered Pi accumulation phenotypes, suggesting that these plants could potentially serve to remove Pi from Pi-rich soils. Our study addresses the long-term impacts of PP-InsP reduction on plant growth, as well as establishing a starting material for a unique Pi reclaiming cover crop. SIGNIFICANCE STATEMENTA major challenge to food security is the phosphorus (P) crisis. A global P shortage is imminent based on the misuse of current resources and will be further aggravated by climate change and a lack of policy addressing sustainability. Our work addresses this crisis by investigating the sustained impact of altering inositol pyrophosphates to manipulate plant P accumulation, a strategy that could be used to remediate nutrient-polluted environments.

plant biology↗

bioRxiv2020

Thyroid hormone regulates proximodistal identity in the fin skeleton

Across the [~]30,000 species of ray-finned fish, fins show incredible diversity in overall shape and in the patterning of the supportive bony rays. Fin length mutant zebrafish have provided critical insights into the developmental pathways that regulate relative fin size. However, the processes that govern skeletal patterning along the proximodistal axis of the fin have remained less well understood. Here, we show that thyroid hormone regulates proximodistal identity of fin rays, distalizing gene expression profiles, morphogenetic processes during outgrowth, and ultimate morphology of the fin. This role for thyroid hormone in specifying proximodistal identity appears conserved between development and regeneration, in all the fins, and between species. We demonstrate that proximodistal identity is regulated independently from pathways that determine size, and we show that modulating proximodistal patterning relative to growth can recapitulate the spectrum of fin ray diversity found in nature.

developmental biology↗

bioRxiv2019

Thyroid hormone coordinates developmental trajectories but does not underlie developmental truncation in Danionins

BackgroundChanges in post-embryonic developmental trajectories can profoundly alter adult phenotypes and life history transitions. In vertebrate clades with complex, biphasic life cycles, thyroid hormone (TH) regulates metamorphosis, and alterations to TH metabolism underlie famous cases of paedomorphosis. We tested the requirement for TH in multiple post-embryonic developmental processes in the zebrafish, and asked if TH loss was associated with paedomorphosis in miniaturized Danionellas. ResultsWe found that TH regulates the relative growth of different body parts in zebrafish, inhibiting head growth at juvenile stages. The lateral line also showed sensitivity to the hormone: head neuromasts were inhibited by TH, while trunk neuromasts required TH for their proliferation. While several aspects of Danionella morphology resembled that of larval zebrafish, these species did not resemble hypothyroid zebrafish in their shape or lateral line, and these fish showed functional thyroid follicles. ConclusionsAlthough zebrafish do not undergo a discrete ecological transformation, we found that multiple tissues go through a protracted metamorphosis, and that TH ushers in growth patterns and processes typical of juveniles. We found no evidence that compromised TH metabolism is responsible for paedomorphosis in Danionellas. Nonetheless, modulations to TH-sensitive pathways affect evolutionarily-relevant traits, and are likely important targets for adaptation. Bullet PointsO_LIThyroid hormone regulates shifts in relative growth trajectories in different zebrafish tissues C_LIO_LIThyroid hormone inhibits head growth in juvenile zebrafish, and regulates juvenile growth patterns C_LIO_LIThyroid hormone stimulates formation of neuromast canals in the head and stitches on the trunk of zebrafish C_LIO_LIDanionella, the miniaturized sister group to Danio morphologically resemble larval zebrafish and do not form neuromast canals C_LIO_LIHypothyroidism is not the cause of paedomorphosis in Danionella C_LI Grant SponsorsNIH R00GM105874 NIH R03HD091634 Burroughs Wellcome Collaborative Research Travel Grant 1017439

developmental biology↗