Biology subjects

van Soldt, B. J.

Publications and source records attributed to van Soldt, B. J..

3 recordsLinked to original sources

bioRxiv2024

KLHDC7B, a novel gene associated with age-related hearing loss in humans, is required for the maintenance of hearing in mice.

BackgroundAge-related hearing loss (ARHL) is the most common sensory loss in older adults, but the underlying pathological mechanisms remain unclear. Recent genome wide association studies (GWAS) have linked variation in a large number of genes with increased risk of ARHL for the first time. Amongst the strongest of these associations is variation in KLHDC7B, a gene of unknown function and one not previously linked to hearing. MethodsTo confirm whether KLHDC7B plays a role in hearing we investigated auditory function in two independent knockout mutant mouse models of Klhdc7b: Klhdc7bIMPC-/-and Klhdc7bRegn{Delta}/{Delta} on the C57BL/6N background and the B6.CAST-Cdh23753A>G background respectively. The B6.CAST-Cdh23753A>G background was backcrossed to correct a known age-related hearing loss (ahl) mutation in cadherin 23 present in both the C57BL/6N and C57BL/6J strains. ResultsWe showed that Klhdc7b is expressed exclusively in inner and outer sensory hair cells within the cochlea of mice at the RNA and protein level. Homozygous mutants for both knockout mouse models display a similar early-onset, progressive and severe hearing loss. Histological characterization of the two mouse models suggests that hair cells develop normally and are present in neonates. However, after the onset of hearing there is a progressive loss of outer hair cells in a gradient from base to apex of the cochlea consistent with the hearing deficit in the mice and the pattern of hearing loss in ARHL. Inner hair cells remain intact up to the latest age examined (~8 weeks). ConclusionsOur data suggests KLHDC7B is required for maintenance of auditory function rather than in its development, supporting the novel association with ARHL in humans detected in recent GWAS. To our knowledge, this is the first validation in mouse of an ARHL association in humans detected in a GWAS. Our work also provides two distinct mouse models to further investigate the role of KLHDC7B in auditory function and for use in the development of therapeutic tools to prevent or treat ARHL.

genetics↗

bioRxiv2022

Single Cell Multimodal Analyses Reveal Epigenomic and Transcriptomic Basis for Birth Defects in Maternal Diabetes

Birth defects occur in [~]6% of all live births and can be caused by combinations of genetic and environmental influences1. Large-scale DNA sequencing efforts are revealing genetic influences2,3, but investigations into the contributions of environmental factors have largely been limited to association studies with limited mechanistic insight. Hyperglycemia present in pre-gestational diabetic mothers is among the most frequent environmental contributor to congenital defects and results in an increased incidence of congenital heart defects and craniofacial anomalies4. However, the cell types involved and underlying mechanisms by which maternal hyperglycemia affects these regions are unknown. Here, we utilized multi-modal single cell analyses to reveal that maternal diabetes affects the epigenomic and transcriptomic state of specific subsets of cardiac and craniofacial progenitors during embryogenesis. A previously unrecognized subpopulation of anterior heart field progenitors expressing Alx3 acquired a more posterior identity in response to maternal hyperglycemia, based on gene expression and chromatin status. Similarly, a sub-population of neural crest-derived cells in the second pharyngeal arch, which contributes to craniofacial structures, also displayed abnormalities in cell specification and patterning. Analysis of differentially accessible chromatin regions demonstrated that disrupted patterning was associated with increased intrinsic retinoic acid signaling in affected cell types in response to maternal diabetes and hyperglycemia. This work demonstrates how an environmental insult can have highly selective epigenomic consequences on discrete cell types leading to developmental patterning defects.

developmental biology↗

bioRxiv2021

The mechanical and morphological properties of systemic and pulmonary arteries differ in the earth boa, a snake without ventricular pressure separation

The walls of the mammalian aorta and pulmonary artery are characterized by diverging morphologies and mechanical properties, which has been correlated with high systemic and low pulmonary blood pressures, as a result of intraventricular pressure separation in the mammalian ventricle. However, the relation between intraventricular pressure separation and diverging aortic and pulmonary artery wall morphologies and mechanical characteristics is not understood. The snake cardiovascular system poses a unique model for the study of this question, since representatives both with and without intraventricular pressure separation exist. In this study we perform uniaxial tensile testing on vessel samples taken from the aortas and pulmonary arteries of the earth boa, Acrantophis madagascariensis, a species without intraventricular pressure separation. We then compare these morphological and mechanical characteristics with samples from the ball python, Python regius, and the yellow anaconda, Eunectes notaeus, species with and without intraventricular pressure separation, respectively. Strikingly, we find that although the aortas and pulmonary arteries of A. madagascariensis respond similarly to the same intramural blood pressures, they diverge strongly in morphology, and that this is a common attribute among species without intraventricular pressure separation in this study. In contrast, P. regius aortas and pulmonary arteries diverge both morphologically and in terms of their mechanical properties. Altogether our data indicate that intraventricular pressure separation does not explain diverging aortic and pulmonary artery morphologies. Following the Law of Laplace, we propose that thin pulmonary arteries represent a mechanism to protect the fragile pulmonary vascular bed by reducing the blood volume that passes through, to which genetic factors may contribute more strongly than physiological parameters.

physiology↗