Jessica Rosin

The prevalence of developmental disorders has dramatically increased in Canada and worldwide over the last two decades. While the pervasiveness of developmental disorders in our society can be partly explained by genetics, we are becoming increasingly aware that the environment the fetus is exposed to during pregnancy is critically sensitive to early life exposures and may play a larger role in the rise in developmental disorders than once thought. For example, maternal obesity, stress, infection, and exposure to drugs, chemicals, or air pollution can disrupt fetal development and may result in lifelong consequences. A common feature reported across various human and animal studies examining the impact of maternal perturbations on fetal development relates to disruptions of the immune system, suggesting that immune cells within the developing fetus may sense changes in their surroundings and respond by altering normal developmental programs.

Accordingly, our overarching objective is to understand how distinct populations of immune cells signal to nearby cells during gestation to contribute to proper fetal development. By understanding how immune cells within the fetus contribute to development under normal circumstances, we are better positioned to study what goes awry in cases of maternal challenge or when insults are experienced during gestation. To do this, we employ a variety of experimental approaches to identify unique cell types and the physical means through which they interact with or molecules they use to signal to nearby cells within their surroundings. By disrupting these intricate cellular interactions using genetic knockout lines, pharmacological inhibitors, or environmental insults that perturb the system, we are able study how altering normal developmental programs impacts the fetus.

Neuroscience Research: Extensive proliferation of stem cells and early progenitors is required to generate all of the complex cell types and tissues that comprise the embryo. This often results in the overproduction of cells that need to be removed. Highly dynamic phagocytic immune cells, such as macrophages, exist across all embryonic tissues and are responsible for surveying their surrounding environment to remove dead or dying cells and dispose of cellular debris in order to maintain homeostasis. An emerging body of literature now demonstrates that microglia, the resident macrophages and phagocytic immune cells of the central nervous system (CNS), play an important role during neurodevelopment, beyond phagocytosis and cell removal. 

Project 1: Investigating how maternal stress acts through microglia in a sexually dimorphic manner to disrupt neurodevelopment. My Postdoctoral research and work from others provide evidence that microglia play important and unique roles in development of the hypothalamic brain region. Using single-cell RNA sequencing (scRNAseq), we previously identified four distinct populations of embryonic hypothalamic microglia, one of which is in direct contact with neural stem cells (NSCs) precisely at embryonic day 15.5 (E15.5)—a time at which hypothalamic neurogenesis is terminating and gliogenic programs begin. As microglia are known to quickly respond to pathogenic insults, we exposed pregnant mice to intermittent periods of cold as a form of maternal stress to study how this gestational challenge impacts microglial physiology. Intriguingly, maternal stress elevated NSC-residing microglia numbers, pro-inflammatory cytokine and chemokine secretion, and significantly decreased the number of oxytocin neurons in the paraventricular nucleus (PVN), but only in male embryos. Furthermore, offspring exposed to maternal stress during gestation displayed social deficits, which showed a sex-specific dependency of microglia. This work demonstrates that embryonic microglia play an unappreciated role in translating maternal stressors to sexually dimorphic perturbation of neurodevelopmental programs. Accordingly, Project 1 is targeted at providing mechanistic insight into the sexually dimorphic responsiveness of microglia to maternal stress and further characterizing its impact on neurodevelopment.

Craniofacial Science Research: Considering recent advances in the microglial field highlight the importance of these resident macrophages and phagocytic immune cells to brain development, a fundamental question is whether these same developmental roles evolved in other regions of the embryo, including craniofacial tissues.

Project 2: Characterizing the role CSF1R-expressing cells play in craniofacial development. My Postdoctoral research has shown that depleting CSF1R-expressing cells (i.e., microglia, macrophages, osteoclasts, etc.) during embryogenesis (E3.5 to birth) using the CSF1R inhibitor PLX5622 results in craniofacial and dental abnormalities in postnatal day 21 (P21) and P28 offspring. Specifically, depleting CSF1R-expressing cells during embryogenesis resulted in a distinct doming at the posterior aspect of the cranial vault and the absence of flattening of the mid-cranial vault in PLX5622 exposed animals. Moreover, the upper and lower incisors of PLX5622 exposed offspring lacked typical tooth curvature, displayed distinct notches in the enamel, and showed ectopic enamel ridges. Similarly, the first molars of PLX5622 exposed animals also displayed altered morphology, with a protuberance resembling an extra cusp. These phenotypes were observed in all male and female offspring exposed to the PLX5622 diet during gestation. Considering that macrophages and osteoclasts both express CSF1R, one or more of these cell types could be contributing to the disruptions observed in craniofacial morphogenesis. Accordingly, Project 2 is targeted at understanding how embryonic macrophages and osteoclasts contribute to normal craniofacial development during gestation.

Collaborations

Dr. Annie Vogel Ciernia, Department of Biochemistry and Molecular Biology, Djavad Mowafaghian Centre for Brain Health, UBC: Microglia and neurodevelopmental disorders.
Dr. Christopher Overall, Department of Oral Biological and Medical Sciences, Life Sciences Institute, UBC: Proteomics.
Dr. Joy Richman, Department of Oral Health Sciences, Life Sciences Institute, UBC: Craniofacial development and dysregulation.
Dr. Victor Viau, Department of Cellular and Physiological Sciences, Life Sciences Institute, UBC: Stress-induced activation of the hypothalamic-pituitary-adrenal (HPA) axis.
Dr. Sid Vora, Department of Oral Health Sciences, UBC: Craniofacial development and dysregulation.