Cognitive Function Related to the Sirh11/Zcchc16 Gene Acquired from an LTR Retrotransposon in Eutherians.

Cédric Feschotte,Yui Yamashita,Fumitoshi Ishino,Takaya Abe,Masanobu Yoshikawa,Shigeharu Wakana,Hirotaka Iwafune,Ikuko Yamada,Tamio Furuse,Ryuichi Ono,Tomoko Kaneko-Ishino,Masahito Irie

doi:10.1371/journal.pgen.1005521

Cédric Feschotte, Yui Yamashita + Show 10 more

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https://doi.org/10.1371/journal.pgen.1005521

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Abstract

Gene targeting of mouse S ushi- i chi-related r etrotransposon h omologue 11 / Z inc finger CCHC domain-containing 16 (Sirh11/Zcchc16) causes abnormal behaviors related to cognition, including attention, impulsivity and working memory. Sirh11/Zcchc16 encodes a CCHC type of zinc-finger protein that exhibits high homology to an LTR retrotransposon Gag protein. Upon microdialysis analysis of the prefrontal cortex region, the recovery rate of noradrenaline (NA) was reduced compared with dopamine (DA) after perfusion of high potassium-containing artificial cerebrospinal fluid in knockout (KO) mice. These data indicate that Sirh11/Zcchc16 is involved in cognitive function in the brain, possibly via the noradrenergic system, in the contemporary mouse developmental systems. Interestingly, it is highly conserved in three out of the four major groups of the eutherians, euarchontoglires, laurasiatheria and afrotheria, but is heavily mutated in xenarthran species such as the sloth and armadillo, suggesting that it has contributed to brain evolution in the three major eutherian lineages, including humans and mice. Sirh11/Zcchc16 is the first SIRH gene to be involved in brain function, instead of just the placenta, as seen in the case of Peg10, Peg11/Rtl1 and Sirh7/Ldoc1.

Highlights

Mammals, including human beings, have evolved a unique viviparous reproductive system using a placenta and a highly developed central nervous system
A series of knockout (KO) mouse analyses demonstrated that at least some of the LTR retrotransposon- and retrovirus-derived sequences play essential roles in the current mammalian developmental system as endogenous genes, such as Peg10, Peg11/Rtl1, Sirh7/Ldoc1, SYNCYTINs and FEMATRIN-1, which are active in multiple aspects of placental function
We demonstrate that another LTR retrotransposon-derived gene, Sirh11/Zcchc16, plays an important role in cognitive function in the brain

Summary

Introduction

Mammals, including human beings, have evolved a unique viviparous reproductive system using a placenta and a highly developed central nervous system. How did these unique characteristics emerge in mammalian evolution? In a series of KO mouse experiments we have demonstrated that at least three LTR retrotransposon-derived genes are essential for mammalian development and reproduction via multiple placental functions; Peg is involved in the formation [8] and Peg11/Rtl in the maintenance of the placenta [9], while Sirh7/Ldoc is involved in endocrine regulation via the differentiation/maturation of a variety of placental cells [11], suggesting that they all have profoundly contributed to the evolution of viviparity during mammalian evolution [8,9,10,11, 17, 18]. Among the SIRH family, Sirh11/Zcchc ( called Mart4) is unique because it does not exhibit any placental expression during development, but rather, is expressed in the brain, testis, ovary and kidney

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