Biology subjects

Morris, A. C.

Publications and source records attributed to Morris, A. C..

7 recordsLinked to original sources

bioRxiv2025

Her9 is required for the migration, differentiation, and survival of neural crest cells

Neural crest cells (NCC) are vertebrate-specific multipotent progenitor cells that arise from the neural plate border and go on to contribute to a wide variety of morphological structures such as the jaw and palate, enteric nervous system (ENS), and pigment cells. Defects in essential steps in neural crest cell development have been associated with a wide variety of congenital disorders, collectively referred to as neurocristopathies. Her9/Hes4 is a bHLH-O transcriptional repressor that has been shown to regulate neural crest cell and craniofacial development in Xenopus and zebrafish, however the extent of Her9 function in other neural crest cell lineages has not been investigated. In this study, we characterized NCC phenotypes in her9 mutant zebrafish. We show that loss of Her9 perturbs the development of several NCC derivatives. Her9 mutants display a variety of NCC defects, including craniofacial abnormalities, alterations in pigment cell lineages, and improper formation of the gut. These phenotypes are associated with defects in neural crest cell specification, migration, and differentiation, as well as an upregulation in expression of BMP ligand genes. Furthermore, loss of Her9 leads to apoptosis of NCC derivatives. Collectively, our results show that Her9 functions in neural crest development by regulating members of the NCC gene regulatory network (GRN) to control NCC specification, migration, differentiation and survival.

developmental biology↗

bioRxiv2024

Retinal neuroanatomy of two emerging model organisms, the spiny mouse (Acomys dimidiatus) and the Mongolian gerbil (Meriones unguiculatus)

PurposeDegenerative eye diseases such as macular degeneration and retinitis pigmentosa slowly deteriorate vision, ultimately leading to blindness. Current research with laboratory animal models largely utilizes small mammals that are nocturnal and lack the ability to restore lost vision. In contrast, the Mongolian gerbil is a diurnal rodent with good photopic vision, and the eastern spiny mouse is a small desert-dwelling rodent with remarkable regenerative capabilities. The goal of this study was to identify several antibodies that detect retinal cell classes in Meriones and Acomys, and to describe the retinal anatomy of these two species in comparison to outbred laboratory mice (Mus musculus). MethodsRetinal sections were obtained from adult eyes and subjected to histological or immuno-staining with antibodies for various retinal cell types. Sections were imaged by light, fluorescence, and confocal microscopy, assessing cell number and morphology. Cell density, morphology, and placement were compared between species qualitatively and quantitatively. ResultsImmunohistochemical visualization and analysis of all general classes of retinal neurons and Muller glia revealed a classic assembly of retinal cells with a few deviations compared to Mus. Meriones displayed the highest density of cone photoreceptors and Acomys the lowest. A higher density of bipolar cell bodies in the proximal portion of the inner nuclear layer was observed in both Acomys and Meriones compared to Mus, and both species exhibited an increase in amacrine cell density compared to Mus. ConclusionWe have characterized similarities and differences in the retinal anatomy and cellular density between Meriones, Acomys, and Mus. We identified several commercially available antibodies that reliably detect retinal cell types in the Acomys and Meriones retina. Our results provide a foundation for future research into the visual system adaptations of both of these interesting rodent species.

cell biology↗

bioRxiv2022

Chromatin remodeler Chd7 regulates photoreceptor development and outer segment length

Mutations in the chromatin remodeling factor CHD7 are the predominant cause of CHARGE syndrome, a congenital disorder that frequently includes ocular coloboma. Although CHD7 is known to be required for proper ocular morphogenesis, its role in retinal development has not been thoroughly investigated. Given that individuals with CHARGE syndrome can experience visual impairment even in the absence of coloboma, a better understanding of CHD7 function in the retina is needed. In this study, we characterized the expression pattern of Chd7 in the developing zebrafish and mouse retina and documented ocular and retinal phenotypes in Chd7 loss-of-function mutants. Zebrafish Chd7 was expressed throughout the retinal neuroepithelium when retinal progenitor cells were actively proliferating, and later in subsets of newly post-mitotic retinal cells. At stages of retinal development when most retinal cell types had terminally differentiated, Chd7 expression remained strong in the ganglion cell layer and in some cells in the inner nuclear layer. Intriguingly, strong expression of Chd7 was also observed in the outer nuclear layer where it was co-expressed with markers of post-mitotic cone and rod photoreceptors. Expression of mouse CHD7 displayed a similar pattern, including expression in the ganglion cells, subsets of inner nuclear layer cells, and in the distal outer nuclear layer as late as P15. Two different mutant chd7 zebrafish lines were characterized for ocular and retinal defects. These mutants displayed microphthalmia, reduced numbers of cone photoreceptors, and truncated rod and cone photoreceptor outer segments. Reduced cone photoreceptor number and abnormal outer segments were also observed in heterozygous Chd7 mutant mice. Taken together, our results in zebrafish and mouse reveal a conserved, previously undescribed role for Chd7 in retinal development and photoreceptor outer segment morphogenesis. Moreover, our work suggests an avenue of future investigation into the pathogenesis of visual system defects in CHARGE syndrome. HighlightsO_LIChd7 is expressed in both retinal progenitor cells and in differentiated retinal neurons, including post-mitotic rod and cone photoreceptors. C_LIO_LILoss of Chd7 results in a significant decrease in cone photoreceptors in both zebrafish and mouse. C_LIO_LICone and rod photoreceptor outer segments are truncated in chd7 mutants, suggesting a heretofore unappreciated role for Chd7 in outer segment morphogenesis. C_LI

developmental biology↗

bioRxiv2022

Obesity associated with attenuated tissue immune cell responses in COVID-19

Obesity is common and associated with more severe COVID-19, proposed to be in part related to an adipokine-driven pro-inflammatory state. Here we analysed single cell transcriptomes from bronchiolar lavage in three adult cohorts, comparing obese (Ob, body mass index (BMI) >30m2) and non-obese (N-Ob, BMI <30m2). Surprisingly, we found that Ob subjects had attenuated lung immune/inflammatory responses in SARS-CoV-2 infection, with decreased expression of interferon (IFN), IFN{gamma} and tumour necrosis factor (TNF) alpha response gene signatures in almost all lung epithelial and immune cell subsets, and lower expression of IFNG and TNF in specific lung immune cells. Analysis of peripheral blood immune cells in an independent adult cohort showed a similar, but less marked, reduction in type I IFN and IFN{gamma} response genes, as well as decreased serum IFN, in Ob patients with SARS-CoV-2. Nasal immune cells from Ob children with COVID-19 also showed reduced enrichment of IFN and IFN{gamma} response genes. Altogether, these findings show blunted tissue immune responses in Ob COVID-19 patients, with clinical implications.

immunology↗

bioRxiv2021

Embryonic hyperglycemia perturbs the development of specific retinal cell types, including photoreceptors

Chronic hyperglycemia has been linked to various long-term metabolic disruptions in adults, such as neuropathy, nephropathy, and diabetic retinopathy. According to the 2020 National Diabetes Statistics Report, 10.5% of the US population has diabetes and may be susceptible to long-term complications if blood glucose is not tightly regulated. Further, in 2018, 7.6% of US pregnancies were affected by gestational diabetes, with an average of 1-14% annually [1]. During pregnancy, glucose can pass through the placental barrier, and plays an important role in fetal development and survival. However, excess maternal glucose can also result in diabetic embryopathy. While many studies have examined the teratogenic effects of maternal diabetes on fetal heart development, little is known about the consequences of maternal hyperglycemia on the development of the embryonic retina. To address this question, we investigated retinal cell type differentiation and survival in both a genetic and nutritional model of embryonic hyperglycemia in zebrafish. Strikingly, we found that hyperglycemic larvae displayed a significant reduction in rod and cone photoreceptors and horizontal cells, whereas other retinal neurons were not affected. We also observed signs of reactive gliosis in the retinal Muller cells, as well as increased reactive oxygen species (ROS) production in hyperglycemic retinas. Hyperglycemic larvae displayed altered expression of metabolism related genes and had a slower optokinetic response than normoglycemic larvae, indicating altered visual function. Further analysis of early events in retinogenesis revealed a delay in retinal cell differentiation at 48 hpf in hyperglycemic embryos, that coincided with an increase in reactive oxygen species. Taken together, our results suggest that embryonic hyperglycemia results in abnormal retinal cell development via altered timing of retinal cell differentiation and ROS production, which is accompanied by visual defects. As the population with diabetes continues to grow, it is imperative to pinpoint the effects of embryonic hyperglycemia on retinal development. Further studies using zebrafish models of hyperglycemia will allow us to understand the molecular mechanisms underlying these effects, which could aid in the development of therapeutic strategies.

developmental biology↗

bioRxiv2019

Her9/HES4 is required for retinal photoreceptor development, maintenance, and survival

The intrinsic and extrinsic factors that regulate vertebrate photoreceptor specification and differentiation are complex, and our understanding of all the players is far from complete. Her9, the zebrafish ortholog of human HES4, is a basic helix-loop-helix-orange (bHLH-O) transcriptional repressor that regulates neurogenesis in several developmental contexts. We have previously shown that her9 is upregulated during chronic rod photoreceptor degeneration and regeneration in adult zebrafish, but little is known about the role of her9 during retinal development. To better understand the function of Her9 in the retina, we generated zebrafish her9 CRISPR mutants. Her9 homozygous mutants displayed striking retinal phenotypes, including decreased numbers of rods and red/green cones, whereas blue and UV cones were relatively unaffected. The reduction in rods and red/green cones correlated with defects in photoreceptor subtype lineage specification. The remaining rods and double cones displayed abnormally truncated outer segments, and elevated levels of apoptosis. In addition to the photoreceptor defects, her9 mutants also possessed a reduced proliferative ciliary marginal zone, and decreased and disorganized Muller glia. Mutation of her9 was larval lethal, with no mutants surviving past 13 days post fertilization. Our results reveal a previously undescribed role for Her9/Hes4 in photoreceptor differentiation, maintenance, and survival.

developmental biology↗

bioRxiv2018

Capn5 expression in the healthy and regenerating zebrafish retina

PurposeAutosomal dominant neovascular inflammatory vitreoretinopathy (ADNIV) is a devastating inherited autoimmune disease of the eye that displays features commonly seen in other eye diseases, such as retinitis pigmentosa and diabetic retinopathy. ADNIV is caused by a gain of function mutation in Calpain-5 (CAPN5), a calcium dependent cysteine protease. Very little is known about the normal function of Capn5 in the adult retina, and there are conflicting results regarding its role during mammalian embryonic development. The zebrafish (Danio rerio) is an excellent animal model for studying vertebrate development and tissue regeneration, and represents a novel model to explore the function of Capn5 in the eye.\n\nMethodsWe characterized the expression of Capn5 in the developing zebrafish central nervous system (CNS) and retina, in the adult zebrafish retina, and in response to photoreceptor degeneration and regeneration using whole mount in situ hybridization, fluorescent in situ hybridization (FISH), and immunohistochemistry.\n\nResultsIn zebrafish, capn5 is strongly expressed in the developing embryonic brain, early optic vesicles, and in newly differentiated retinal photoreceptors. We found that expression of capn5 co-localized with cone specific markers in the adult zebrafish retina. We observed an increase in expression of Capn5 in a zebrafish model of chronic rod photoreceptor degeneration and regeneration. Acute light damage to the zebrafish retina, was accompanied by an increase in expression of Capn5 in the surviving cones and in a subset of Muller glia.\n\nConclusionsThese studies suggest that Capn5 may play a role in CNS development, photoreceptor maintenance, and photoreceptor regeneration.

developmental biology↗