Biology subjects

Hickey, S. L.

Publications and source records attributed to Hickey, S. L..

4 recordsLinked to original sources

bioRxiv2024

Smad4 is essential for epiblast scaling and morphogenesis after implantation, but nonessential prior to implantation in the mouse

Bone Morphogenic Protein (BMP) signaling plays an essential and highly conserved role in axial patterning in embryos of many externally developing animal species. However, in mammalian embryos, which develop inside the mother, early development includes an additional stage known as preimplantation. During preimplantation, the epiblast lineage is segregated from the extraembryonic lineages that enable implantation and development in utero. Yet, the requirement for BMP signaling in mouse preimplantation is imprecisely defined. We show that, in contrast to prior reports, BMP signaling (as reported by SMAD1/5/9 phosphorylation) is not detectable until implantation, when it is detected in the primitive endoderm - an extraembryonic lineage. Moreover, preimplantation development appears normal following deletion of maternal and zygotic Smad4, an essential effector of BMP signaling. In fact, mice lacking maternal Smad4 are viable. Finally, we uncover a new requirement for zygotic Smad4 in epiblast scaling and cavitation immediately after implantation, via a mechanism involving FGFR/ERK attenuation. Altogether, our results demonstrate no role for BMP4/SMAD4 in the first lineage decisions during mouse development. Rather, multi-pathway signaling among embryonic and extraembryonic cell types drives epiblast morphogenesis post-implantation. Summary StatementGene expression, gene deletion, and pathway visualization evidence show that Smad4-dependent signaling is first active after mouse embryo implantation, when it promotes epiblast morphogenesis non-cell autonomously.

developmental biology↗

bioRxiv2024

OCT4 is expressed in extraembryonic endoderm stem (XEN) cell progenitors during somatic cell reprogramming

During development, progenitors of embryonic stem (ES) and extraembryonic endoderm stem (XEN) cells are concomitantly specified within the inner cell mass (ICM) of the mouse blastocyst. Similarly, XEN cells are induced (iXEN cells) alongside induced pluripotent stem (iPS) cells following overexpression of Oct4, Sox2, Klf4 and Myc (OSKM) during somatic cell reprogramming. It is unclear how or why this cocktail produces both stem cell types, but OCT4 has been associated with non-pluripotent outcomes. In this report, we show that, during OSKM reprogramming, many individual Oct4-GFP-expressing cells are fated to become iXEN cells. Interestingly, SKM alone was also sufficient to induce iXEN cell formation, likely via activation of endogenous Oct4. These observations indicate that iXEN cell formation is not strictly an artifact of Oct4 overexpression. Moreover, our results suggest that a pathway to XEN may be an integral feature of establishing pluripotency during reprogramming, as in early embryo development.

developmental biology↗

bioRxiv2022

A network-based drug repurposing approach identifies new treatment opportunities for the systemic chronic inflammation underlying multiple complex diseases

Complex diseases are associated with a wide range of cellular, physiological, and clinical phenotypes. To advance our understanding of disease mechanisms and our ability to treat these diseases, it is critical to delineate the molecular basis and therapeutic avenues of specific disease phenotypes, especially those that are associated with multiple diseases. Inflammatory processes constitute one such prominent phenotype, being involved in a wide range of health problems including ischemic heart disease, stroke, cancer, diabetes mellitus, chronic kidney disease, non-alcoholic fatty liver disease, and autoimmune and neurodegenerative conditions. While hundreds of genes might play a role in the etiology of each of these diseases, isolating the genes involved in the specific phenotype (e.g., inflammation "component") could help us understand the genes and pathways underlying this phenotype across diseases and predict potential drugs to target the phenotype. Here, we present a computational approach that integrates gene interaction networks, disease-/trait-gene associations, and drug-target information to accomplish this goal. We apply this approach to isolate gene signatures of complex diseases that correspond to chronic inflammation and prioritize drugs to reveal new therapeutic opportunities.

bioinformatics↗

bioRxiv2019

Cortical Foxp2 supports behavioral flexibility and developmental dopamine D1 receptor expression

Genetic studies have associated FOXP2 variation with speech and language disorders and other neurodevelopmental disorders involving pathology of the cortex. In this brain region, FoxP2 is expressed from development into adulthood, but little is known about its downstream molecular and behavioral functions. Here, we characterized cortex-specific Foxp2 conditional knockout mice and found a major deficit in reversal learning, a form of behavioral flexibility. In contrast, they showed normal activity levels, anxiety, and vocalizations, save for a slight decrease in neonatal call loudness. These behavioral phenotypes were accompanied by decreased cortical dopamine D1 receptor (D1R) expression at neonatal and adult stages, while general cortical development remained unaffected. Finally, using single-cell transcriptomics, we identified at least five excitatory and three inhibitory D1R-expressing cell types in neonatal frontal cortex, and we found changes in D1R cell type composition and gene expression upon cortical Foxp2 deletion. Strikingly, these alterations included non-cell-autonomous changes in upper-layer neurons and interneurons. Together these data support a role for Foxp2 in the development of dopamine-modulated cortical circuits and behaviors relevant to neurodevelopmental disorders.

neuroscience↗