hnRNPL expression dynamics in the embryo and placenta.

Heterogeneous nuclear ribonucleoprotein L (hnRNPL) is a conserved RNA binding protein (RBP) that plays an important role in the alternative splicing of gene transcripts, and thus in the generation of specific protein isoforms. Global deficiency in hnRNPL in mice results in preimplantation embryonic lethality at embryonic day (E) 3.5. To begin to understand the contribution of hnRNPL-regulated pathways in the normal development of the embryo and placenta, we determined hnRNPL expression profile and subcellular localization throughout development. Proteome and Western blot analyses were employed to determine hnRNPL abundance between E3.5 and E17.5. Histological analyses supported that the embryo and implantation site display distinct hnRNPL localization patterns. In the fully developed mouse placenta, nuclear hnRNPL was observed broadly in trophoblasts, whereas within the implantation site a discrete subset of cells showed hnRNPL outside the nucleus. In the first-trimester human placenta, hnRNPL was detected in the undifferentiated cytotrophoblasts, suggesting a role for this factor in trophoblast progenitors. Parallel in vitro studies utilizing Htr8 and Jeg3 cell lines confirmed expression of hnRNPL in cellular models of human trophoblasts. These studies [support] coordinated regulation of hnRNPL during the normal developmental program in the mammalian embryo and placenta.

Interaction of extraembryonic microglia and neonatal brain development.

Microglia are resident immune cells in the central nervous system (CNS), which, in a healthy state, promote CNS homeostasis and respond to CNS injury. In contrast, microglia are also implicated in pathological conditions where they may contribute to neural damage. Primitive microglia arise from extraembryonic progenitors in the yolk sac (YS). The extraembryonic origins of primitive microglia are distinct from other tissue macrophages. The YS is the first site of hematopoiesis in development. Uniquely, microglial pregenital cells in the mouse derive from an early myeloid branch of the hematopoietic lineage in the YS. Microglia are critical in several key stages of physiological brain development, including embryonic vasculogenesis, immunosurveillance, and neurogenesis. Abnormal microglial function has been linked to neurodevelopmental and neurodegenerative diseases, although mechanistic roles in disease etiology remain incompletely understood. Knowledge of species-specific differences between human, murine and other animal models is also critical to understanding translational relevance to human health and disease as biomedical understanding of the importance of primitive microglia advances. This significance drives the importance of understanding, comparatively, the extraembryonic origins and developmental mechanisms whereby human primitive microglia differentiate and migrate to inform translational research. A better understanding of the molecular drivers may lead to biomarkers and/or preventative or therapeutic measures for neonatal brain development and neurodegenerative diseases. Herein, the role of microglia in neonatal brain development is discussed, current understandings of the developmental origins of microglia are described, the ontogeny and phylogeny of microglia, and implications of in vitro microglia-like cell differentiation, with a specific interest on neurodegenerative diseases, are reviewed. Together, these emphasize the importance of leveraging the extraembryonic origins of microglia to not only better understand neurodevelopment and neurodegenerative diseases, but also to develop protective measures that are specific to human microglia.