Biology subjects

Hardin, A.

Publications and source records attributed to Hardin, A..

3 recordsLinked to original sources

bioRxiv2025

A gene expression atlas of a juvenile nervous system

Although the fundamental architecture of metazoan nervous systems is typically established in the embryo, substantial numbers of neurons are added during post-natal development while existing neurons expand in size, refine connectivity, and undergo additional differentiation. To reveal the underlying molecular determinants of postembryonic neurogenesis and maturation, we have produced gene expression profiles of all neuron types and their progenitors in the first larval stage (L1) of C. elegans. Comparisons of the L1 profile to the embryo and to the later L4 larval stage identified thousands of differentially expressed genes across individual neurons throughout the nervous system. Key neuropeptide signaling networks, for example, are remodeled during larval development. Gene regulatory network analysis revealed potential transcription factors driving the temporal changes in gene expression across the nervous system, including a broad role for the heterochronic transcription factor lin-14. We utilized available connectomic data of juvenile animals in combination with our neuron-specific atlas to identify potential molecular determinants of membrane contact and synaptic connectivity. These expression data are available through a user-friendly interface at CeNGEN.org for independent investigations of the maturation, connectivity and function of a developing nervous system.

neuroscience↗

bioRxiv2020

Dynamics of Prion Proliferation Under CombinedTreatment of Pharmacological Chaperones andInterferons via a Mathematical Model

Prion diseases are lethal neurodegenerative disorders such as mad cow disease in bovines, chronic wasting disease in cervids, and Creutzfeldt-Jakob disease in humans. They are caused when the prion protein PrPC misfolds into PrPSc, which is capable of inducing further misfolding in healthy PrPC proteins. Recent in vivo experiments show that pharmacological chaperones can temporarily prevent this conversion by binding to PrPC molecules, and thus constitute a possible treatment. A second strategic approach uses interferons to decrease the concentration of PrPSc. In order to study the quantitative effects of these treatments on prion proliferation, we develop a model using a non-linear system of ordinary differential equations. By evaluating their efficacy and potency, we find that interferons act at lower doses and achieve greater prion decay rates. However, there are benefits in combining them with pharmacological chaperones in a two-fold therapy. This research is crucial to guide future prion experiments and inform potential treatment protocols.Competing Interest StatementThe authors have declared no competing interest.View Full Text

cell biology↗

bioRxiv2017

Promoter Or Enhancer Activation By CRISPRa Rescues Haploinsufficiency Caused Obesity

Haploinsufficiency, having only one functional copy of a gene, leads to a wide range of human disease and has been associated with over 300 genes. Here, we tested whether CRISPR activation (CRISPRa) could rescue a haploinsufficient disease in vivo. Haploinsufficiency of Sim1, a transcription factor involved in the leptin pathway, results in severe obesity in humans and mice. CRISPRa targeting of either the Sim1 promoter or its ~270kb distant hypothalamic enhancer using transgenic mice, rescued the obesity phenotype in Sim1 heterozygous mice. Interestingly, despite using a ubiquitous promoter for CRISPRa, Sim1 was upregulated only in tissues where the promoter or enhancer are active, suggesting that cis-regulatory elements can determine CRISPRa tissue-specificity. To further relate this to therapy, we injected CRISPRa adeno associated virus into the hypothalamus, leading to reversal of the obesity phenotype. This therapeutic strategy could be used to rescue numerous diseases resulting from altered gene dosage.

genetics↗