Biology subjects

Sheridan, M.

Publications and source records attributed to Sheridan, M..

3 recordsLinked to original sources

bioRxiv2026

Age dependent impairment of home cage behavior and reactivity in Cntnap2 knock out mouse model

Contactin-associated protein-like 2 (CNTNAP2) is a transmembrane protein that mediates neuron-glia interactions and regulates dendritic spine growth and neuronal migration. Mutations in the CNTNAP2 gene are linked to autism and epilepsy. Younger Cntnap2 KO mice mimic autism phenotypes, while older mice are a model for epilepsy. Thus, comparing behavioral phenotypes across different ages is needed to better understand the age dependent development of disordered brain networks in Cntnap2 mutants. Male and female Cntnap2 KO and WT controls were tested across different age groups (4, 5, 7, 9, and [~]11 months) using digging, stimulus (reactivity), and nesting assays. Older Cntnap2 KO mice (7, 9, and [~]11 months) showed a significant increase in home cage reactivity (stimulus) assay compared to younger mice at 4 and 5 months of age. Similar trends were observed in male and female Cntnap2 KO mice. No significant differences were observed in WT controls. A significant difference in digging assay was observed in KO female mice between younger (4 month) and older mice post nest removal. An age-dependent significant reduction in nesting behavior was observed in female KO mice; however, no difference was observed in the WT controls. Immunohistochemical analysis showed age dependent change interneuron and microglial network in Cntnap2 KO mice. Our findings suggest disruption in home cage behavior and reactivity in older pre-epileptic Cntnap2 KO mice indicating an age-dependent network alteration and behavior deficits. Significance StatementThis study investigates the age-dependent behavioral changes in Cntnap2 KO mice due to underlying changes in the neuronal network. It has been shown that younger Cntnap2 KO mice display autistic behaviors and that older Cntnap2 KO mice have epilepsy, but it is unknown how behavior is affected during the intervening period of epileptogenesis. We find that female Cntnap2 KO mice at 11 months of age have increased reactivity and decreased motor activity compared to younger age groups, whereas WT mice show no relationship between age and behavior. Overall, the loss of Cntnap2 alters behavior in an age-dependent and sex-specific manner, indicating progressive dysregulation of the neuronal network.

neuroscience↗

bioRxiv2023

Successful placentation in human pregnancy is regulated by reciprocal interactions between maternal uterine NK cells and fetal placental trophoblast

Fetal growth and development during human pregnancy depends on delivery of adequate maternal oxygen and nutrients to the fetus via the placenta. In humans, the balanced invasion of fetal placental trophoblast cells into the maternal uterine lining, where they interact with uterine natural killer cells (uNK), is thought to be critical for a successful pregnancy but exactly how this influences reproductive outcomes remains undefined. Here, we used our trophoblast organoid model and primary tissue samples to determine how uNK affect placentation. By locating potential interaction axes between primary trophoblast cells and uNK using single cell transcriptomics, and in vitro modelling of these interactions in trophoblast organoids, we identify a uNK-derived cytokine signal that promotes trophoblast differentiation by enhancing epithelial-mesenchymal transition and increasing trophoblast cells at the late stage of the invasive pathway. Moreover, it affects transcriptional programs involved in increasing blood flow, placental access to nutrients, and dampening inflammatory and adaptive immune responses, as well as gene signatures associated with disorders of pregnancy such as pre-eclampsia. Our findings shed new light on how optimal immunological interactions between maternal uNK cells and fetal trophoblast enhance reproductive success.

developmental biology↗

bioRxiv2022

The Musashi proteins are post-transcriptional activators of protein expression and alternative exon splicing in vertebrate photoreceptors

The Musashi proteins, MSI1 and MSI2, are conserved RNA binding proteins with a role in the maintenance and renewal of stem cells. Contrasting with this role, retina and terminally differentiated photoreceptor cells express high levels of MSI1 and MSI2, indicating that the two proteins have a role unrelated to maintaining undifferentiated cell state. Here we show that the Musashi proteins are essential in mature photoreceptors. Combined knockout of Msi1 and Msi2 lead to loss of the retina response to light and progressive photoreceptor cell death. The two proteins are fully redundant as individual deletion of Msi1 or Msi2 did not produce a phenotype. To define the molecular functions underlying the requirement for Musashi in photoreceptors, we delineated their RNA targets and analyzed the effect of the combined Msi1/Msi2 knockout on transcript levels, pre-mRNA splicing, and protein expressions. We show distinct nuclear and cytoplasmic functions for the Musashi proteins in photoreceptor cells. In the nucleus, Musashi binding to the downstream proximal intron promotes splicing of alternative exons. Surprisingly, four conserved photoreceptor-specific alternative exons in genes critical for vision proved to be dispensable, leaving open questions about the selective pressures that lead to the conservation of these exons and the contribution of alternative splicing to the phenotype of the Musashi knockout. In the photoreceptor cell cytoplasm MSI1 and MSI2 act as activators of protein expression. The combined knockout of Msi1 and Msi2 reduced the levels of multiple proteins including proteins required for vision and photoreceptor survival.

neuroscience↗