Role of Cell Death in the Development of Sex Differences
Several of the best-studied sex differences are differences in cell number. Circumstantial evidence suggests that these sex differences are due to differential cell death in males and females, but to test this idea directly we took advantage of cell death mutant mice. We find that some neural sex differences are completely eliminated in mice lacking the pro-death gene, Bax, or over-expressing the pro-survival gene, Bcl-2. Other sex differences persist unabated in cell death mutants, demonstrating that processes other than cell death (such as the differentiation of phenotype) are responsible.
Holmes MM, Niel L, Anyan JJ, Griffith AT, Monks DA, Forger NG. 2011. Effects of Bax gene deletion on social behaviors and response to olfactory cues in mice. European Journal of Neuroscience
de Vries GJ, Jardon M, Reza M, Rosen GJ, Immerman E, Forger NG. 2008. Sexual differentiation of vasopressin innervation of the brain: cell death versus phenotypic differentiation. Endocrinology 149: 4632-4637.
Forger NG, Rosen GJ, Waters EM, Jacob D, Simerly RB, de Vries GJ. 2004. Deletion of Bax eliminates sex differences in the mouse forebrain. Proceedings of the National Academy of Sciences, USA 101:13666-13671.
Microglia and Cell Death
Microglia are the primary immune cells of the central nervous system. They constantly survey the brain and rapidly become “activated” in response to any disturbance. Microglia contribute to neuronal cell death in mouse models of neurodegenerative diseases or following brain injury. Less is known about the role of microglia in naturally-occuring cell death during normal development. We are testing whether microglia are involved in the timing and magnitude of cell death in the neonatal mouse brain, and determining whether microglia are neurotoxic or neuroprotective during this period.
Cell Death Atlas
Naturally occurring cell death is a critical process during the development of the nervous system. In mammals, about 50% of the neurons originally produced die by apoptosis. Although it is clear that developmental apoptosis is important for the fine tuning of neural circuits, many basic questions are still unanswered, such as what triggers developmental cell death. Recently we created a cell death “atlas” detailing the patterns of cell death in the ventral forebrain of the mouse from embryonic day 17 (two days before birth) to postnatal day 11. The patterns of postnatal cell death have been published in the citation below. A commonly observed pattern was for highest levels of cell death to be observed right around the time of birth, which led to the next project described below. [FOR MORE DETAILS ON THIS PROJECT, OR TO REQUEST ACCESS TO THE ATLAS SLIDES, PLEASE SEE THE “ATLAS” TAB ABOVE.]
Ahern TH, Krug S, Carr AV, Murray E, Fizpatrick E, Bengston L, McCutcheon J, De Vries GJ, Forger NG. 2013. Cell death atlas of the postnatal mouse ventral forebrain and hypothalamus: Effects of age and sex. Journal of Comparative Neurology 521:2551-2569.
Mosley M, Shah C, Morse KA, Miloro SA, Holmes MM, Ahern TH, Forger NG. 2017. Patterns of cell death in the perinatal mouse forebrain. Journal of Comparative Neurology 525:47-64.
Birth and Brain Development
Cell death peaks around the time of birth in several brain regions of the mouse. In addition, preliminary data show that natural (vaginal) birth might be important for the normal course of cell death because Cesarean born mice have decreased cell death in several brain regions compared to vaginally born mice. Birth entails a dramatic entry to the world and, in preparation, key peripheral organs (e.g., lungs, gut, and heart) undergo physiological changes. We hypothesize that birth is also an important event in brain development, for example, by triggering cell death. In this project, we are studying how birth influences cell death in the brain by manipulating the timing or mode of birth in mice. We are also interested in identifying mechanisms underlying cell death at birth, as well as exploring additional effects of birth on brain development and behavior.