The Maternal Immune Axis Programs Fetal Corticogenesis

This project seeks to elucidate sex-specific mechanisms by which maternal immune activation (MIA) during pregnancy impacts cortical development and elevates the risk for neurodevelopmental disorders (NDDs), focusing specifically on the CXCR7 (Ackr3)/CXCL12 chemokine signaling axis. MIA, triggered by maternal infection or inflammation, is a known risk factor for conditions such as autism spectrum disorder and schizophrenia, with male offspring often showing increased vulnerability and differing symptom profiles compared to females. The molecular basis of these sex differences remains poorly understood, representing a critical knowledge gap in both developmental neurobiology and translational medicine. Aim 1 will investigate the physiological role of the CXCR7/CXCL12 axis in corticogenesis, examining how sex-specific regulation of CXCR7 affects neural progenitor cell (NPC) differentiation and migration. By employing Ackr3 knockout models and epigenetic profiling, we will determine how CXCR7 signaling is modulated in male and female NPCs, which may underlie differences in cortical organization between the sexes. Aim 2 will examine the pathophysiological role of CXCR7/CXCL12 in response to MIA, testing the hypothesis that MIA induces a male-specific upregulation of CXCR7 that leads to aberrant cortical development and behaviors associated with NDDs. We will use advanced molecular techniques to assess how CXCR7 activation in males contributes to cortical disorganization, precocious NPC maturation, and behavioral changes, as well as to evaluate the dependency of these effects on maternal IL-17 signaling. Together, these aims will provide mechanistic insights into how intrinsic sex differences interact with environmental factors like MIA to shape brain development and vulnerability to NDDs. This work is significant because it addresses an urgent need to understand how intrinsic sex differences and external maternal immune influences jointly shape neurodevelopmental trajectories. This research ultimately aims to bridge a gap in neurodevelopmental disorder research by providing a clearer understanding of how male and female brains respond differently to environmental stressors during critical periods of development, which may have lasting implications for public health and clinical care. Project Number: 1R01MH138484-01A1 | Fiscal Year: 2026 | NIH Institute/Center: National Institute of Mental Health (NIMH) | Principal Investigator: Yeong Shin Yim | Institution: UNIVERSITY OF PENNSYLVANIA, PHILADELPHIA, PA | Award Amount: $689,249 | Activity Code: R01 | Study Section: Special Emphasis Panel[ZRG1 CN-X (85)] View on NIH RePORTER: https://reporter.nih.gov/project-details/11225200