Yale Study Shows PUM1 and PUM2 Help Older Brains Gain New Cells

The absence of two key genes dramatically shrinks the number of neural stem cells (right). Credit: Yale University

A newly published study from Yale University identified two genes that are crucial to the creation of neurons in the brain region responsible for learning and memory.

Two genes act as molecular midwives to the birth of neurons in adult mammals and when inactivated in mice cause symptoms of Fragile X Syndrome, a major cause of mental retardation, a new Yale University study has shown.

In humans as well as mice, most neurons are created prior to birth and few new brain cells are produced as adults. The new study identified two genes that are crucial to the creation of neurons in the brain region responsible for learning and memory. When the two Pumilio genes — PUM1 and PUM2 — are knocked out in mice, few neural stem cells are created in this region, which becomes very small. The mice can no longer navigate mazes and exhibit the same pathology as humans with Fragile X Syndrome.

The genes control whether RNA that has already been transcribed actually goes on to create proteins, a little studied step of gene regulation with major biological implications, said senior author Haifan Lin, the Eugene Higgins Professor of Cell Biology, and professor of genetics and of obstetrics, gynecology, and reproductive sciences as well as director of the Yale Stem Cell Center.

Meng Zhang, a graduate student in the Lin lab, was the lead author of the study published on August 15 in Genes & Development.

Reference: “Post-transcriptional regulation of mouse neurogenesis by Pumilio proteins” by Meng Zhang, Dong Chen, Jing Xia, Wenqi Han, Xiekui Cui, Nils Neuenkirchen, Gretchen Hermes, Nenad Sestan and Haifan Lin, 15 August 2017, Genes & Development.
DOI: 10.1101/gad.298752.117

Abstract: Despite extensive studies on mammalian neurogenesis, its post-transcriptional regulation remains under-explored. Here we report that neural-specific inactivation of two murine post-transcriptional regulators, Pumilio 1 (Pum1) and Pum2, severely reduced the number of neural stem cells (NSCs) in the postnatal dentate gyrus (DG), drastically increased perinatal apoptosis, altered DG cell composition, and impaired learning and memory. Consistently, the mutant DG neurospheres generated fewer NSCs with defects in proliferation, survival, and differentiation, supporting a major role of Pum1 and Pum2 in hippocampal neurogenesis and function. Cross-linking immunoprecipitation revealed that Pum1 and Pum2 bind to thousands of mRNAs, with at least 694 common targets in multiple neurogenic pathways. Depleting Pum1 and/or Pum2 did not change the abundance of most target mRNAs but up-regulated their proteins, indicating that Pum1 and Pum2 regulate the translation of their target mRNAs. Moreover, Pum1 and Pum2 display RNA-dependent interaction with fragile X mental retardation protein (FMRP) and bind to one another’s mRNA. This indicates that Pum proteins might form collaborative networks with FMRP and possibly other post-transcriptional regulators to regulate neurogenesis.