Biology subjects

Harkins, D.

Publications and source records attributed to Harkins, D..

3 recordsLinked to original sources

bioRxiv2025

RARS1 integration into the multisynthetase complex is crucial for mammalian brain development

Aminoacyl tRNA synthetases occupy a central role in protein synthesis by charging tRNAs with their cognate amino acid. Eight aminoacyl-tRNA synthetases with nine enzymatic activities form a large protein complex but the breadth of functions mediated by the multisynthetase complex remains elusive. Neurological disorders have been associated with mutations within the domain tethering Arginyl-tRNA synthetase (RARS1) to the multisynthetase complex, which offers an interesting bridge between protein synthesis and neurodevelopment. To interrogate this connection, we developed a mouse model where RARS1 is excluded from the multisynthetase complex in the forebrain. We observed profound disruptions in neural development as attested by drastically reduced forebrain size and behavioral deficits. At the molecular level, neurodevelopmental and ribosomal genes were dysregulated. Finally, the subcellular localization of RARS1 and its colocalization with other translational machinery components were perturbed. Altogether, our results reveal the necessity of RARS1 integration in the multisynthetase complex for proper neurodevelopment.

molecular biology↗

bioRxiv2023

Polycomb Repressive Complex 2 is critical for mouse cortical glutamatergic neuron development

The Polycomb Repressive Complex 2 (PRC2) regulates corticogenesis, yet the consequences of mutations to this epigenetic modifier in the mature brain are poorly defined. Importantly, PRC2 core genes are haploinsufficient and causative for several human neurodevelopmental disorders. To address the role of PRC2 in mature cortical structure and function, we conditionally mutated the PRC2 gene Eed in the developing mouse telencephalon. Adult homozygotes displayed smaller forebrain structures. Single-nucleus transcriptomics revealed glutamatergic neurons were particularly affected, exhibiting dysregulation of cortical layer-specific profiles, accompanied by aberrations in neuronal morphology and connectivity. Incredibly, homozygous mice performed well on challenging cognitive tasks. In contrast, heterozygous mice did not exhibit anatomical or behavioral phenotypes but displayed dysregulation of neuronal genes and altered neuronal morphology that was strikingly different from homozygous phenotypes. Collectively, we demonstrate how alterations to PRC2 function shape the mature brain and reveal a dose-specific role for PRC2 in determining glutamatergic neuron identity.

developmental biology↗

bioRxiv2018

Supragingival plaque microbiome ecology and functional potential in the context of health and disease

To address the question of how microbial diversity and function in the oral cavities of children relates to caries diagnosis, we surveyed the supragingival plaque biofilm microbiome in 44 juvenile twin pairs. Using shotgun sequencing, we constructed a genome encyclopedia describing the core supragingival plaque microbiome. Caries phenotypes contained statistically significant enrichments in specific genome abundances and distinct community composition profiles including strain-level changes. Metabolic pathways that are statistically associated with caries include several sugar-associated phosphotransferase systems, antimicrobial resistance, and metal transport. Numerous closely-related previously-uncharacterized microbes had substantial variation in central metabolism, including the loss of biosynthetic pathways resulting in auxotrophy, changing the ecological role. We also describe the first complete Gracilibacteria genomes from the human microbiome. Caries is a microbial community metabolic disorder that cannot be described by a single etiology and our results provide the information needed for next generation diagnostic tools and therapeutics for caries.

microbiology↗