Takashi Kohda

Retrotransposon Gag-like (RTL) 8A, 8B and 8C are eutherian-specific genes derived from a certain retrovirus. They clustered as a triplet of genes on the X chromosome, but their function remains unknown. Here, we demonstrate that Rtl8a and Rtl8b play important roles in the brain: their double knockout (DKO) mice not only exhibit reduced social responses and increased apathy-like behavior, but also become obese from young adulthood. Mouse RTL8A/8B proteins are expressed in the prefrontal cortex and hypothalamus and localize to both the nucleus and cytoplasm of neurons, presumably due to the N-terminal nuclear localization signal-like sequence at the N-terminus. An RNAseq study in the cerebral cortex revealed reduced expression of several GABA type A receptor subunits, in particular the β2 subunit of Gabrb2, in DKO. We confirmed the reduction of GABRB2 protein in the DKO cerebral cortex by Western blotting. As GABRB2 has been implicated in the etiology of several neurodevelopmental disorders, it is likely that the reduction of GABRB2 is one of the major causes of the neuropsychiatric defects in the DKO mice.

Retrotransposon Gag-like ( RTL ) 8A, 8B and 8C are triplet genes of uncertain function that form a cluster on the X chromosome. They are eutherian-specific genes presumably derived from a certain retrovirus. Here, we demonstrate that Rtl8a and Rtl8b play an important role in growth and behavior via brain functions in the hypothalamus and prefrontal cortex. Rtl8a and Rtl8b double knockout (DKO) mice exhibited overgrowth due to hyperphagia from young adulthood and reduced social responses, increased apathy-like behavior. RTL8A and RTL8B proteins are localized to both the nucleus and cytoplasm of neurons presumably due to an N-terminal nuclear localization signal-like sequence. An increment in nucleus size was also detected in the neurons in the prefrontal cortex, suggesting neuronal dysfunction. These data give another strong evidence that retrovirus-derived acquired genes contributed to the establishment of the current eutherian developmental system in a wide variety of ways. Summary statement: Rtl8a and Rtl8b double knockout mice exhibited late onset obesity and neurodevelopmental defects, demonstrating that these eutherian specific retrovirus-derived acquired genes encoding proteins with only 113 amino acids play important roles in the brain presumably via their functions in the hypothalamus and prefrontal cortex.

The therian-specific gene paternally expressed 10 (Peg10) plays an essential role in placenta formation: Peg10 knockout mice exhibit early embryonic lethality as a result of severe placental defects. The PEG10 protein exhibits homology with long terminal repeat (LTR) retrotransposon GAG and POL proteins; therefore, we generated mice harboring a mutation in the highly conserved viral aspartic protease motif in the POL-like region of PEG10 because this motif is essential for the life cycle of LTR retrotransposons/retroviruses. Intriguingly, frequent perinatal lethality, not early embryonic lethality, was observed with fetal and placental growth retardation starting mid-gestation. In the mutant placentas, severe defects were observed in the fetal vasculature, where PEG10 is expressed in the three trophoblast cell layers that surround fetal capillary endothelial cells. Thus, Peg10 has essential roles, not only in early placenta formation, but also in placental vasculature maintenance from mid- to late-gestation. This implies that along the feto-maternal placenta interface an interaction occurs between two retrovirus-derived genes, Peg10 and retrotransposon Gag like 1 (Rtl1, also called Peg11), that is essential for the maintenance of fetal capillary endothelial cells.

The effect of space radiation on offspring was evaluated using mouse freeze-dried spermatozoa preserved on the Space Station.

The therian-specific gene paternally expressed 10 ( Peg10 ) plays an essential role in placenta formation: Peg10 knockout (KO) mice exhibit early embryonic lethality due to severe placental defects. The PEG10 protein exhibits homology to long terminal repeat (LTR) retrotransposon GAG and POL proteins, therefore mice harboring a mutation in its highly conserved viral aspartic protease motif in the POL-like region were generated because it is essential for LTR retrotransposons/retroviruses. Intriguingly, frequent perinatal lethality, not early embryonic lethality, was observed with fetal and placental growth retardation starting mid-gestation. In the mutant placentas, severe defects were observed in the fetal vasculature, where PEG10 is expressed in the three trophoblast cell layers that surround fetal capillary endothelial cells. Thus, Peg10 has essential roles not only in early placenta formation, but also in placental vasculature maintenance from mid- to late-gestation. This implies that along the feto-maternal placenta interface an interaction occurs between two retrovirus-derived genes, Peg10 and retrotransposon Gag like 1 ( Rtl1, also called Peg11 ), that is essential for the maintenance of fetal capillary endothelial cells. Summary statement: Disruption of the highly conserved viral aspartic protease domain in PEG10 causes placental abnormality leading to perinatal lethality in mice.

Local control of sperm maturation: Newly produced spermatozoa within the testis do not have fertilizing ability but become fully functional when they mature in the epididymis. The development of the epididymis itself is dependent on testicular factors arriving via luminal flow. Improper signaling between the testis and epididymis is hypothesized to result in male infertility. Kiyozumi et al. identified NELL2 as a testicular luminal protein that binds to its receptor, ROS1, on the luminal epididymis surface and induces epididymal differentiation (see the Perspective by Lord and Oatley). In turn, differentiated epididymis secretes a fertility-essential protease, ovochymase-2, to make spermatozoa fully mature and functional. Thus, testis-epididymis interorgan communication by this “lumicrine” regulation ensures mammalian reproduction. Science , this issue p. 1132 ; see also p. 1053

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The placenta is critical in mammalian embryonic development because the embryo’s supply of nutrients, including amino acids, depends solely on mother-to-embryo transport through it. However, the molecular mechanisms underlying this amino acid supply are poorly understood. In this study, we focused on system A amino acid transporters Slc38a1 /SNAT1, Slc38a2 /SNAT2, and Slc38a4 /SNAT4, which carry neutral, short-side-chain amino acids, to determine their involvement in placental or embryonic development. A triple-target CRISPR screen identified Slc38a4 /SNAT4 as the critical amino acid transporter for placental development in mice. We established mouse lines from the CRISPR founders with large deletions in Slc38a4 and found that, consistent with the imprinted paternal expression of Slc38a4 /SNAT4 in the placenta, paternal knockout (KO) but not maternal KO of Slc38a4 /SNAT4 caused placental hypoplasia associated with reduced fetal weight. Immunostaining revealed that SNAT4 was widely expressed in differentiating cytotrophoblasts and maturing trophoblasts at the maternal–fetal interface. A blood metabolome analysis revealed that amino acid concentrations were globally reduced in Slc38a4 /SNAT4 mutant embryos. These results indicated that SNAT4-mediated amino acid transport in mice plays a major role in placental and embryonic development. Given that expression of Slc38a4 in the placenta is conserved in other species, our Slc38a4 /SNAT4 mutant mice could be a promising model for the analysis of placental defects leading to intrauterine growth restriction in mammals.

An actinomycete strain, TKZ-21T, was isolated from a freshwater alga (Chetophoraceae) collected from the Takizawa River, Yamanashi, Japan, and examined using a polyphasic taxonomic approach. Cells were Gram-stain positive, aerobic, non-sporulating, motile, and coccoid or short rod-shaped. The strain grew in the presence of 0–4 % (w/v) NaCl, between pH 6–9.4, and over a temperature range of 15–40 °C, with optimum growth at 30 °C. The peptidoglycan type of strain TKZ-21T was A4β, containing l-ornithine as diagnostic diamino acid and d-glutamic acid as the interpeptide bridge. The predominant menaquinone was MK-9(H4). The polar lipids were diphosphatidylglycerol, phosphatidylglycerol, ninhydrin-positive glycolipid, and unidentified phospholipids. The major cellular fatty acids were anteiso-C15 : 0 and anteiso-C17 : 0, and the DNA G+C content was 75.6 mol%. On the basis of 16S rRNA gene sequence analysis, strain TKZ-21T was closely related to Cellulomonas fimi (98.5 % sequence similarity) and Cellulomonas biazotea (98.3 %). The genome orthoANI value between strain TKZ-21T and C. biazotea and C. fimi were 84.7 and 84.2 %, respectively. On the basis of fatty acid and MALDI-TOF MS profile analysis, phylogenetic analyses, genomic analysis, and phenotypic data, it is proposed that the isolate be classified as a representative of a novel species of the genus Cellulomonas , with the name Cellulomonas algicola sp. nov. The type strain is TKZ-21T (=NBRC 112905T=TBRC 8129T).