The role of the endogenous retroviral family, IAP, in placentation.

ABSTRACT
Endogenous retroviruses (ERVs) constitute 10% of all genomes, yet they remain the wild west of
biology, even though they function within the host cell in a myriad of critical ways, including as regulatory
elements, as extracellular messengers, as sources of viral-like particles (VLPs), and, importantly, as somatic
mutagens. Our overreaching goal is to understand how the ERV family, IAP (Intracisternal type A Protein),
functions at the mouse maternal-fetal interface. Thousands of genomic IAP instances exist that consist of gag,
pro, pol sequences flanked by LTRs. These instances have lost the ancestral envelope (env) sequence and
form naked VLPs that remain inside the cell and can transpose. Today, only a single copy, IAPE-D1, remains
with a conserved envelope (env) sequence that mediates extracellular release of its VLPs. This strong
evolutionary conservation of the env in IAPE-D1 suggests that it serves an important extracellular function.
Thus, IAPs function in two distinct cellular domains: one as an extracellular messenger, and the other as an
intracellular source of regulation and mutation.
The rigor of prior research strongly supports this hypothesis. More than 50 years ago VLPs were
described in placentas of all species, including mouse and human. The source of the mouse VLPs is likely IAP
as we find that it is the only ERV family expressed during placentation. Our data suggests that these VLPs are
functional as, when we knock down IAP using shRNA in trophoblast stem cells (TSCs) or in mouse embryos,
we observe defects in differentiation and placentation. Further, we find that IAP binds specific RNAs in TSCs,
including those that mediate differentiation and imprinting, suggesting that IAP VLPs contain cargo.
Importantly, we find that IAP protein is expressed in maternal tissues in the absence of transcript, suggesting
that it was transported from the neighboring placental cells. Based on our own preliminary results and more
than 50 years of prior research on IAP, we hypothesize that 1) the only extracellular IAP, IAPE-D1, is forming
VLPs in the mouse placenta that transport specific RNAs into the maternal decidua and 2) the intracellular
IAPs serve multiple functions including the generation of naked VLPs that are mutagenic and as sequences
that serve as critical regulatory elements within the placenta genome. While human placentas do not have IAP,
they do have HERVK, which forms VLPs that are likely to serve similar functions especially given that the
placenta is a hotspot for convergent evolution. Overall, this proposal will deliver the function and mechanism
of a major fraction of the unexplored genome during pregnancy.

Grant Number: 5R01HD110888-04
NIH Institute/Center: NIH
Principal Investigator: Julie Baker