"The physiological role of poly(A)-binding protein-interacting protein 1" Dr. Akiko YANAGIYA.

Speaker: Dr. Ayako Yanagiya

Goodman Cancer Research Centre, McGill University, Montreal, Quebec, CANADA

Title: The physiological role of poly(A)-binding protein-interacting protein 1 in male germ cell development and memory formation

Abstract: Translational control of mRNAs plays a critical role in cell growth and proliferation, and enables cells to respond rapidly to growth and proliferation stimuli, stress, and nutrient availability. The rate-limiting step of translation is the recognition of the cap structure at the 5’ end of mRNA by the cap-binding complex, eukaryotic translation initiation factor 4F (eIF4F) and the subsequent recruitment of ribosome. eIF4F consists of a cap-binding protein, eIF4E, a scaffold protein, eIF4G and an RNA helicase, eIF4A. Translation is also facilitated by circularization of the mRNA via the interaction between eIF4G and poly(A)-binding protein (PABP) at the 3’ end of mRNA.

PABP plays a pivotal role in translation and mRNA stability, and its activity is regulated by PABP-interacting proteins (PAIPs) such as PAIP1 and PAIP2. PAIP1 has been characterized as a positive translational regulator that associates with other translational factors such as PABP and eIF3. PAIP1 contributes to the stabilization of the circular mRNA and the recruitment of ribosome via eIF3. The interaction between PAIP1 and eIF3 is regulated by the mTOR/S6K pathway. PAIP1 contains PABP-interacting motifs 2 (PAM2) at the N-terminus, the middle domain of eIF4G (MIF4G) and PAM1 at the C-terminus, whose contributions to translational regulation remain elusive.

In mice, PAIP1 is highly expressed in brain, testis, lung, spleen, thymus and white adipose tissues. Little is known about its physiological functions in these tissues. To reveal the physiological role of PAIP1, Paip1-knockout (KO) mice were generated using the CRISPR/Cas9 genome editing.

Intriguingly, male Paip1-KO mice are infertile because of aberrant sperm formation. PAIP1 is mainly expressed in pachytene spermatocytes, implying an impaired translational regulation during early germ cell development by the lack of PAIP1. In accordance with PAIP1 expression in pachytene spermatocytes, postmitotic round spermatids are dissociated from pachytene spermatocytes, which results in spermatid malformations during later male germ cell development.

Translational control plays a pivotal role in synaptic plasticity and memory formation in which a labile short-term memory is converted into a persistent long-term memory. PAIP1 is expressed in the cytoplasm of cell body and dendrites of neurons in hippocampus. To investigate the possible role of PAIP1 in memory consolidation, Paip1-KO mice were subjected to contextual fear conditioning, a hippocampal-dependent task with a foot shock. Interestingly, Paip1-KO mice froze less than WT littermates, demonstrating an impairment of long-term contextual memory in Paip1-KO mice.

In summary, my study will provide insight into translational regulations in key physiological processes such as male germ cell development and memory formation.

Host:

Tadashi Yamamoto, Cell Signal Unit