Biology subjects

Presnell, J. S.

Publications and source records attributed to Presnell, J. S..

6 recordsLinked to original sources

bioRxiv2024

Increased Netrin downstream of overactive Hedgehog signaling disrupts optic fissure formation

BackgroundUveal coloboma, a developmental eye defect, is caused by failed development of the optic fissure, a ventral structure in the optic stalk and cup where axons exit the eye and vasculature enters. The Hedgehog (Hh) signaling pathway regulates optic fissure development: loss-of-function mutations in the Hh receptor ptch2 produce overactive Hh signaling and can result in coloboma. We previously proposed a model where overactive Hh signaling disrupts optic fissure formation by upregulating transcriptional targets acting both cell- and non-cell-autonomously. Here, we examine the Netrin family of secreted ligands as candidate Hh target genes. ResultsWe find multiple Netrin ligands upregulated in the zebrafish ptch2 mutant during optic fissure development. Using a gain-of-function approach to overexpress Netrin in a spatiotemporally specific manner, we find that netrin1a or netrin1b overexpression is sufficient to cause coloboma and disrupt wild-type optic fissure formation. We used loss-of-function alleles, CRISPR/Cas9 mutagenesis, and morpholino knockdown to test if loss of Netrin can rescue coloboma in the ptch2 mutant: loss of netrin genes does not rescue the ptch2 mutant phenotype. ConclusionThese results suggest that Netrin is sufficient but not required to disrupt optic fissure formation downstream of overactive Hh signaling in the ptch2 mutant. Key FindingsO_LIOveractive Hedgehog signaling in the ptch2 mutant causes increased netrin expression C_LIO_LISpatiotemporally specific overexpression of netrin1a and netrin1b can cause coloboma C_LIO_LISpatiotemporally specific overexpression of netrin1a can disrupt optic fissure and stalk formation as well as optic stalk cell morphology, similar to the ptch2 mutant C_LIO_LILoss of netrin ligands in the ptch2 mutant does not rescue the phenotype C_LI

developmental biology↗

bioRxiv2022

Rapid reduction of Paraoxonase expression followed by inactivation across semiaquatic mammals suggests adaptive benefit of gene loss

Convergent adaptation to the same environment by multiple lineages frequently involves rapid evolutionary change at the same genes, implicating these genes as important for environmental adaptation. Such adaptive molecular changes may yield either change or loss of protein function; loss of function can eliminate newly deleterious proteins or reduce energy necessary for protein production. We previously found a striking case of recurrent pseudogenization of the Paraoxonase 1 (Pon1) gene among aquatic mammal lineages - Pon1 became a pseudogene with genetic lesions, such as stop codons and frameshifts, at least four times independently in aquatic and semiaquatic mammals. Here, we assess the landscape and pace of pseudogenization by studying Pon1 sequences, expression levels, and enzymatic activity across four aquatic and semiaquatic mammal lineages: pinnipeds, cetaceans, otters, and beavers. We observe in beavers and pinnipeds an unexpected reduction in expression of Pon3, a paralog with similar expression patterns but different substrate preferences. Ultimately, in all lineages with aquatic/semiaquatic members, we find that preceding any coding level pseudogenization events in Pon1, there is a drastic decrease in expression, followed by relaxed selection, thus allowing accumulation of disrupting mutations. The recurrent loss of Pon1 function in aquatic/semiaquatic lineages is consistent with a benefit to Pon1 functional loss in aquatic environments. Accordingly, we examine diving and dietary traits across pinniped species as potential driving forces of Pon1 functional loss. We find that loss is best correlated with diving activity and likely results from changes in selective pressures associated with hypoxia and hypoxia-induced inflammation.

evolutionary biology↗

bioRxiv2022

Molecular insights into the Darwin paradox of coral reefs from the sea anemone Aiptasia

Symbiotic cnidarians such as corals and anemones form highly productive and biodiverse coral-reef ecosystems in nutrient-poor ocean environments, a phenomenon known as Darwins Paradox. Resolving this paradox requires elucidating the molecular bases of efficient nutrient distribution and recycling in the cnidarian-dinoflagellate symbiosis. Using the sea anemone Aiptasia, we show that during symbiosis, the increased availability of glucose and the presence of the algae jointly induce the coordinated upregulation and re-localization of glucose and ammonium transporters. These molecular responses are critical to support symbiont functioning and organism-wide nitrogen assimilation through GS/GOGAT-mediated amino-acid biosynthesis. Our results reveal crucial aspects of the molecular mechanisms underlying nitrogen conservation and recycling in these organisms that allow them to thrive in the nitrogen-poor ocean environments. One-sentence summaryWhole-organism nitrogen assimilation fueled by glucose from symbiotic algae enables corals to flourish in oligotrophic waters.

molecular biology↗

bioRxiv2022

Highly Dynamic Gene Family Evolution Suggests Changing Roles for PON Genes Within Metazoa

Change in gene family size has been shown to facilitate adaptation to different selective pressures. This includes gene duplication to increase dosage or diversification of enzymatic substrates and gene deletion due to relaxed selection. We recently found that the PON1 gene, an enzyme with arylesterase and lactonase activity, was lost repeatedly in different aquatic mammalian lineages, suggesting that the PON gene family is responsive to environmental change. We further investigated if these fluctuations in gene family size were restricted to mammals and approximately when this gene family was expanded within mammals. Using 112 metazoan protein models, we explored the evolutionary history of the PON family to characterize the dynamic evolution of this gene family. We found that there have been multiple, independent expansion events in tardigrades, cephalochordates, and echinoderms. In addition, there have been partial gene loss events in monotremes and sea cucumbers and what appears to be complete loss in arthropods, urochordates, platyhelminths, ctenophores, and placozoans. In addition, we show the mammalian expansion to three PON paralogs occurred in the ancestor of all mammals after the divergence of sauropsida but before the divergence of monotremes from therians. We also provide evidence of a novel PON expansion within the brushtail possum. In the face of repeated expansions and deletions in the context of changing environments, we suggest a range of selective pressures, including pathogen infection and mitigation of oxidative damage, are likely influencing the diversification of this dynamic gene family across metazoa.

evolutionary biology↗

bioRxiv2019

Krüppel-like factor gene function in the ctenophore Mnemiopsis suggests an ancient role in promoting cell proliferation in metazoan stem cell niches

The Kruppel-like factor (Klf) gene family encodes for transcription factors that play an important role in the regulation of stem cell proliferation, cell differentiation, and development in bilaterians. While Klf genes have been shown to functionally specify various cell types in non-bilaterian animals, their role in early diverging animal lineages has not been assessed. Thus, the ancestral activity of these transcription factors in animal development is not well understood. The ctenophore Mnemiopsis leidyi has emerged as an important non-bilaterian model system for understanding early animal evolution. Here we characterize the expression and functional role of Klf genes during M. leidyi embryogenesis. Zygotic Klf gene function was assessed with both CRISPR/Cas9-mediated genome editing and splice-blocking morpholino oligonucleotide knockdown approaches. Abrogation of zygotic Klf expression during M. leidyi embryogenesis results in abnormal development of several organs including the pharynx, tentacle bulbs, and apical organ. Our data suggest an ancient role for Klf genes in regulating endodermal patterning, possibly through regulation of cell proliferation. Summary StatementUsing CRISPR/Cas9 genome editing and morpholino oligonucleotide knockdown, this study shows that tissues derived from the endoderm are dependent upon Klf5 ortholog expression for proper development and patterning in the ctenophore Mnemiopsis leidyi.

developmental biology↗

bioRxiv2017

Reduction in major transcription factor binding domain families during the evolution of the avian lineage

Transcription factors are characterized by their domain architecture, including DNA binding and protein-protein interaction domain combinations, which regulate their binding specificity, as well as their ability to effect a change on gene expression of their downstream targets. Transcription factors are central to organismal development, thus they potentially are instrumental in producing phenotypic diversity. Transcription factor abundance was estimated via 49 major DNA binding domain families, as well as 34 protein-protein interaction domain families, in 48 bird genomes, which were then compared with 6 available reptile genomes, in an effort to assess the degree to which these domains are potentially connected to increased phenotypic diversity in the avian lineage. We hypothesized that there would be increased abundance in multiple transcription factor domain families, as well as domains associated with protein-protein interactions, that would correlate with the increased phenotypic diversity found in birds; instead, this data shows a general loss/contraction of major domain families, with the largest losses in domain families associated with multiple developmental (feather, body-plan, immune) and metabolic processes. Ultimately, the results of this analyses represent a general characterization of domain family composition in birds, thus the specific domain composition of TF families should be probed further, especially those with the largest reductions seen in this study.

evolutionary biology↗