Macrophage progenitors colonize their anatomical niches in the central nervous system (CNS) in distinct pre- and postnatal waves. Microglia progenitors originate from early erythromyeloid progenitors in the yolk sac and enter the murine CNS around embryonic day (E)9.5. While their developmental origin is well established, the molecular mechanisms guiding CNS colonization are not yet resolved. Using transcriptomic and proteomic approaches, we identified potential factors involved in this process. Microglia progenitors showed a distinct integrin surface profile and transmigrate along the extracellular matrix (ECM)-enriched pial surface into the CNS, pointing to a mesenchyme-to-CNS migration route. Loss of the integrin adaptor protein talin-1 in microglia progenitors led to a reduced CNS colonization, whereas macrophage progenitors in the surrounding mesenchyme remained unchanged. Overall, our data suggest that microglial progenitors enter the CNS parenchyma via talin-1-mediated migration from the surrounding mesenchyme through the ECM-enriched pial surface.
Two recent studies reveal that TMK receptor kinases directly phosphorylate and stabilize PIN auxin exporters in plants, forming rapid feedback loops that reinforce directional auxin flow. Together, these papers uncover a unifying mechanism in which auxin perception at the plasma membrane instructs PIN polarity, transport efficiency, and self-organizing growth behavior.
Major depressive disorder (MDD) is a complex, multifactorial neuropsychiatric disorder influenced by both genetic and environmental factors, but how these factors impact human neuronal function remains unclear. Using a highly defined human pluripotent stem cell (hPSC)-based prefrontal cortex (PFC) platform, we examined three high-confidence environmental and genetic factors associated with depression: chronic exposure to high levels of cortisol or interferon alpha (IFN-a), and a mutation in SIRTUIN 1 (SIRT1). All three conditions induced overlapping phenotypes of neuronal dysfunction, characterized by dendritic atrophy, synaptic loss, and neuronal hypoactivity across multiple cell lines. RNA sequencing uncovered converging alterations in neuronal cholesterol homeostasis. Depleting cholesterol in control neurons reproduced core depression-associated neuronal phenotypes, while cholesterol supplementation was sufficient to rescue these phenotypes in depression-associated conditions. These findings point to cholesterol imbalance as a common driver of neuronal dysfunction in MDD, linking diverse genetic and environmental risk factors through a shared cellular pathway.
How do ci-regulatory differences, across mouse subspecies and over evolutionary timescales, shape cell-type specification and maturation during corticogenesis? In this issue of Developmental Cell, Medina-Cano et al. establish a scalable mouse organoid platform that recapitulates developmental dynamics and enables mapping of allele-specific expression, linking cis-regulatory variation with neurodevelopmental mechanisms and disease-associated genetics.
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