REGULATION OF STEM CELL TRANSITIONS IN THE DEVELOPING FOREBRAIN

How do neural stem cells go through developmental transitions to generate neurons and glia, the major functional units of the brain? We are currently focused on cellular and molecular mechanisms that guide transitions during the development of the cerebral cortex, the highest processing center of the brain. Our lab has been studying important mechanisms that regulate the proliferation of progenitors and migration of their progeny in the embryonic cerebral cortex and postnatal olfactory bulbs. We previously identified the zinc finger transcription factor Specificity Protein 2 (Sp2) as a potent regulator of cell cycle progression and differentiation in both the cortex and olfactory bulbs (Liang et al., Development, 2013; Loziuk et al., 2016; Johnson et al., 2020). Our studies employed genetic mice to conditionally ablate various Sp factors in a cell-specific manner and have yielded novel mechanisms that regulate cell cycle progression and couple it to mechanisms of cytokinesis, cell adhesion, and other exciting cell biological phenomena. The intersection of these cell biological events are critical for transition of stem cells from a proliferative mode of division (symmetric) to neurogenic differentiative (asymmetric) divisions. The lab is hard at work in determining how and to what extent Sp family members cooperate to accomplish this critical developmental transition. (Supported by NIH R01 NS089795).

More recently we have identified factors involved with the later transition of neural stem cells into becoming gliogenic progenitors. Again, we are focused on the forebrain as the tissue of interest. Using sophisticated mouse genetic approaches we have defined the role of the epidermal growth factor receptor (Egfr) in this important transition both at the the level of individual progenitors (clonal) and populations of progenitors in the cerebral cortices (Beattie et al., 2017; Zhang et al., 2020). We are currently employing these approaches to precisely define the role of gliogenesis and other factors involved in this important transition in development of distinct regions of the forebrain and their effects on behavioral development and homeostasis. (Supported by NIH R01 NS08795 and NIH R56 NS117019).

Along the way, we have started collaborating with Engineers and Mass Spectrometric experts such as Drs. Greenbaum and Muddiman to develop high throughput and analytical platforms that interphase with our biological data for thorough and unbiased understnding of our experimental results. For example, we are developing novel and exciting new tissue clearning and analytical tools for understanding the high content brain images we capture in our projects (Li et al., 2021, 2022; Cai et al., 2021). We also continue to develop new in-tissue mass spectrometry methods for detection of lipids and proteins to enhance our understanding of mechanims involved in developmental transitions understudy in our lab (Loziuk et al., 2017).