Regulation of Neuronal Maturation and Apoptosis by Micrornas

Apoptosis, or programmed cell death, is a conserved and highly regulated pathway by which cells die. This form of cell death is important for normal development and is critical for maintaining tissue homeostasis by eliminating cells that are superfluous, no longer useful, or harmful for the organism. Apoptosis is particularly important both for the development and maintenance of post-mitotic neurons. Rather surprisingly, many neurons must undergo apoptosis for the nervous system to develop properly and to precisely match neurons with their appropriate target cells. However, it is also necessary that apoptosis is strictly inhibited in neurons after development ends. Since neurons must survive and function for the entire life of the organism, it is absolutely necessary that these cells develop mechanisms to inhibit apoptosis. Here, I investigated the mechanisms developed by neurons during their maturation which inhibit apoptosis in these cells. Specifically, I focused on whether a class of molecules called microRNAs are important for the regulation of apoptosis as neurons mature. While some of the mechanisms that become engaged to promote survival of mature neurons are known, virtually nothing is understood of how microRNAs regulate this process. Importantly, I discovered that a microRNA, called miR-29b, becomes induced with neuronal maturation and is able to inhibit apoptosis by regulating a key family of pro-apoptotic genes. This work provides the first example of a mammalian microRNA that can inhibit apoptosis in neurons. In contrast to the expression of miR-29b, which increases greatly during neuronal maturation, the vast majority of other microRNAs become markedly downregulated during the maturation process. Thus, I have also focused on testing whether this global decrease of microRNAs is involved in the regulation of apoptosis in mature neurons. It is critical to gain an understanding of the mechanisms evolved by neurons to inhibit apoptosis during their maturation because these mechanisms are likely to be critical for the long-term survival of neurons. The failure to inhibit apoptosis in mature neurons would be catastrophic, as these irreplaceable cells would become more vulnerable neurodegenerative disease. The work presented here describes newly discovered mechanisms involving microRNAs which are important for neuronal survival.Doctor of Philosoph