Biology subjects

Rosin, J. M.

Publications and source records attributed to Rosin, J. M..

5 recordsLinked to original sources

bioRxiv2026

Live-cell imaging of fetal microglia reveals time-dependent sex differences in their responsiveness to prenatal maternal stress

Prenatal maternal stress is increasingly being linked to neurodevelopmental disorders (NDDs), and across diverse maternal stressors, immune dysregulation is emerging as a common feature. This suggests that fetal microglia may influence neurodevelopment by detecting changes in signaling from the intrauterine environment. Using a mouse model of prenatal maternal stress, where pregnant mice were exposed to cold from embryonic day 11.5 (E11.5) to E15.5, we previously demonstrated that fetal microglia show region-specific and morphology-dependent sex differences in their responsiveness to prenatal maternal stress using static analyses. Here, we extend these analyses by conducting live-cell imaging on the E15.5 hypothalamic paraventricular nucleus (PVN) to assess microglial morphology, motility, and phagocytic behavior in real-time under homeostatic conditions and in response to prenatal maternal cold stress exposure. Prenatal maternal cold stress induced sex- and time-specific changes in microglial morphology in the PVN, where female microglia showed increased branch complexity across the entire live-cell video recording, while male microglia only showed this response at early time-points. Interestingly, PVN microglia also showed baseline sex differences in phagocytic behavior, with male microglia showing higher phagocytic activity as compared to female microglia. In response to prenatal maternal cold stress, male microglia showed a decrease in completed phagocytic events in the PVN, whereas female microglia showed increased engagement in phagocytic activity with no change in completed phagocytic events. Microglial motility was also altered in the PVN of female embryos at early time-points in response to prenatal maternal cold stress, but no such changes were observed in males. Together, these data demonstrate that fetal microglia show sex differences in key physiologies both at baseline and in response to prenatal maternal cold stress. Through time-resolved assessment of microglial dynamics, our findings also suggest that microglial responsiveness to prenatal maternal cold stress differs between males and females, which may help to provide a cellular basis for sex differences observed across many NDDs.

neuroscience↗

bioRxiv2026

Fetal microglia show region-specific and morphology-dependent sex differences in their responsiveness to prenatal maternal stress

The prevalence of neurodevelopmental disorders (NDDs) has increased dramatically, with growing evidence linking prenatal maternal stress exposure to NDDs. Across diverse maternal stressors, immune dysregulation emerges as a common feature, suggesting that fetal microglia may detect changes in the intrauterine environment and influence neurodevelopment. Accordingly, we utilized a mouse model of prenatal maternal cold stress to investigate the impact of maternal stress during pregnancy on fetal microglia morphology, cellular interactions, and phagocytic behaviors. Pregnant mice were exposed to cold stress from embryonic day 11.5 (E11.5) to E15.5 and fetal hypothalamic tissue was assessed from both male and female embryos. By adapting the morphology analysis toolset MicrogliaMorphology to assess fetal microglia, we demonstrate regional differences in microglial morphology in the fetal hypothalamus at baseline, with hypothalamic nuclei such as the paraventricular nucleus (PVN) containing fewer rod-like microglia compared to the broader hypothalamus. Interestingly, prenatal maternal cold stress induced a male-specific shift in microglial morphology from ameboid to ramified within the E15.5 PVN. Male embryos also displayed increased microglial-arginine vasopressin (AVP) neuronal interactions and microglial phagocytosis within the E15.5 PVN, but these changes were unique to microglia with a ramified morphology and were not observed when microglia with an ameboid or rod-like morphology were assessed. Using pHrodo bioparticles and flow cytometry, we further illustrate that prenatal maternal cold stress drives increased phagocytic activity in the E15.5 hypothalamus of male embryos, but not females. Together, these data demonstrate that prenatal maternal cold stress alters microglia morphology and drives morphology-dependent microglial interactions and phagocytic behaviors in male embryos which are unique to the hypothalamic PVN--a nuclei critical for social behaviors. Our findings also suggest that specific hypothalamic nuclei such as the PVN may be more sensitive to prenatal maternal stress, which has the potential to provide a cellular basis underlying the sex differences in microglia-dependent social deficits that were previously reported for this model.

neuroscience↗

bioRxiv2026

Prenatal exposure to maternal stress drives sex-specific neurodevelopmental disruptions in the fetal hypothalamus

The hypothalamus plays a central role in integrating physiological stressors to maintain homeostasis, yet how fetal neurodevelopment in the hypothalamus is shaped by intrauterine maternal stress exposure remains understudied. This is especially true in the context of sex-divergent mechanisms underlying neurodevelopmental disorders (NDDs), which are increasingly being linked to perturbation of the intrauterine environment. Herein, we utilize a mouse model of prenatal maternal cold stress exposure to study the impacts on neural stem and progenitor cell (NSPC) developmental programs in the fetal hypothalamus. Pregnant mice were exposed to cold stress from embryonic day 11.5 (E11.5) to E15.5 and fetal hypothalamic NSPCs from both male and female embryos were analyzed. Exposure to maternal stress altered fetal hypothalamic neurodevelopment, increasing TUJ1+ neuron number in males, while enhancing neuronal dendritic arborization in females. To define underlying molecular changes, we performed single-cell RNA sequencing of hypothalamic NSPCs. Interestingly, we identified distinct baseline transcriptional profiles between male and female NSPCs. In females, maternal stress upregulated pathways related to GABAergic differentiation and neuronal projection morphogenesis, with these alterations being maintained across more differentiated neuronal populations. Ligand-receptor analysis further indicated that maternal stress alters cell-cell communication within NSPCs, predominantly in females. Together, these findings demonstrate that prenatal maternal stress alters hypothalamic NSPC developmental programs uniquely in each sex, and suggest that disrupted intercellular signaling may contribute to underlying sex differences in social behaviors previously reported for this model (Rosin et al., 2021).

developmental biology↗

bioRxiv2025

Gestational inhibition of CSF1R signaling using PLX5622 drives musculoskeletal changes in postnatal offspring

Despite our understanding of the musculoskeletal system under homeostatic conditions and during tissue remodeling, the interplay between muscle and bone development in response to gestational perturbations is less well understood. Here, we used the colony-stimulating factor-1 receptor (CSF1R) inhibitor PLX5622 to disrupt macrophage and osteoclast proliferation, differentiation, and survival during the embryonic period in order to study the impacts on craniofacial development using high-resolution microcomputed tomography (CT). Cranioskeletal and mandibular size and shape were assessed using geometric morphometric (GM) analysis and dense correspondence analysis (DeCA), while contrast-enhanced CT and DeCA were utilized to examine the consequences of prenatal CSF1R inhibition on P1 offspring musculature. Combined, we observed significant disruptions to cranioskeletal and mandibular morphologies, and notable changes in the shape of the muscles of mastication and tongue in newly born pups exposed to the CSF1R inhibitor PLX5622 in utero. By assessing the craniofacial skeleton and associated musculature at birth, we provide a more direct view of how inhibition of CSF1R signaling across embryogenesis contributes to changes in musculoskeletal development during periods of craniofacial morphogenesis.

developmental biology↗

bioRxiv2025

CSF1R+ macrophage and osteoclast depletion impairs neural crest proliferation and craniofacial morphogenesis

Despite a wealth of knowledge on the mechanisms underlying craniofacial morphogenesis during gestation, the roles of fetal macrophages and osteoclasts during this process remain less well characterized. Here, we used the pharmacological inhibitor PLX5622 to disrupt colony stimulating factor-1 receptor (CSF1R) signaling, which is essential for macrophage and osteoclast proliferation, differentiation, and survival. Prenatal PLX5622 exposure resulted in [~]50% depletion of CSF1R+ macrophages, with complete loss of osteoclasts. While there were no notable changes in craniofacial nerve or muscle development, prenatal exposure to PLX5622 resulted in skull doming and cranial suture impairments, in addition to disruptions to development of the premaxilla, mandible, ear ossicles, palate, and cranial base. In response to PLX5622 exposure, cytokine and chemokine signaling was altered and neural crest proliferation was impaired. Our data also highlight sex- and strain-specific differences in PLX5622 phenotypes and together demonstrate that CSF1R+ macrophages and osteoclasts are essential for craniofacial morphogenesis.

developmental biology↗