Post-transcriptional regulation of mouse neurogenesis by Pumilio proteins

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.

Unique repression domains of Pumilio utilize deadenylation and decapping factors to accelerate destruction of target mRNAs

“…Mammalian Pum orthologs have crucial, diverse roles in growth and development, gametogenesis, hematopoiesis, neurogenesis, behavior, motor function and memory formation (97)(98)(99)(100)(101)(102)(103)(104)(105)(106). Their dysfunction has now been linked to cancer, neurodegeneration, epilepsy, memory impairment, reduced fertility, and developmental defects in mammals (97,98,100,103,(107)(108)(109)(110)(111). Thus, we anticipate that further elucidation of Pum function will facilitate better understanding of its role in development and disease, and perhaps inform future therapeutic interventions.…”

Profiling of presynaptic mRNAs reveals a role for axonal PUMILIOs in associative memory formation

“…It is not entirely unexpected that pumilios are in axonal regions. FMRP, which is known to interact with PUM2 (Zhang et al, 2017), is localized in axons during synaptogenesis (Parvin et al, 2019), so it is likely that other FMRP partners also exhibit axonal localization in higher organisms.…”

“…We previously found that molecules that regulate pre-synaptic transport and transmission are important for learning and associative memory formation (Arey et al, 2018;Kaletsky et al, 2016;Lakhina et al, 2015;Li et al, 2016). Furthermore, pumilio is an important regulator of long-term memory in Drosophila (Dubnau et al, 2003), and mammalian PUM1/2 regulate dendrite morphogenesis, synaptic function, neuronal excitability, and hippocampal neurogenesis (Siemen et al, 2011;Vessey et al, 2010;Zhang et al, 2017). We therefore assessed the role of presynaptic pufs in positive olfactory associative memory, in which worms form a positive association with the neutral odorant butanone after pairing with food.…”

A quantitative and predictive model for RNA binding by human Pumilio proteins

“…∆GWT is the affinity for the consensus sequence. (Bohn et al, 2018;Campbell et al, 2012;Campbell et al, 2014;Chen et al, 2012;Dominguez et al, 2018;Elemento et al, 2007;Fazlollahi et al, 2014;Foat et al, 2005;Francischini and Quaggio, 2009;Galgano et al, 2008;Gerber et al, 2004;Gerber et al, 2006;Hafner et al, 2010;Hogan et al, 2015;Jiang et al, 2010;Kershaw et al, 2015;Klass, 2013;Lapointe et al, 2015;Leibovich and Yakhini, 2012;Morris et al, 2008;Opperman et al, 2005;Rabani et al, 2008;Ray et al, 2013;Riordan et al, 2011;Sun et al, 2016;Wilinski et al, 2017;Zhang and Muench, 2015;Zhang et al, 2017). (B) RNA libraries used in this study.…”