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. 2020 Feb;249(2):237-244.
doi: 10.1002/dvdy.125. Epub 2019 Nov 1.

The requirement of SUMO2/3 for SENP2 mediated extraembryonic and embryonic development

H-M Ivy Yu  1 , Trunee Hsu  1   2 , Eri O Maruyama  1 , Wulf Paschen  3 , Wei Yang  3 , Wei Hsu  1   4   5
Affiliations

The requirement of SUMO2/3 for SENP2 mediated extraembryonic and embryonic development

H-M Ivy Yu et al. Dev Dyn. 2020 Feb.

Abstract

Small ubiquitin-related modifier (SUMO)-specific protease 2 (SENP2) is essential for the development of healthy placenta. The loss of SENP2 causes severe placental deficiencies and leads to embryonic death that is associated with heart and brain deformities. However, tissue-specific disruption of SENP2 demonstrates its dispensable role in embryogenesis and the embryonic defects are secondary to placental insufficiency. SENP2 regulates SUMO1 modification of Mdm2, which controls p53 activities critical for trophoblast cell proliferation and differentiation. Here we use genetic analyses to examine the involvement of SUMO2 and SUMO3 for SENP2-mediated placentation. The results indicate that hyper-SUMOylation caused by SENP2 deficiency can be compensated by reducing the level of SUMO modifiers. The placental deficiencies caused by the loss of SENP2 can be alleviated by the inactivation of gene encoding SUMO2 or SUMO3. Our findings demonstrate that SENP2 genetically interacts with SUMO2 and SUMO3 pivotal for the development of three major trophoblast layers. The alleviation of placental defects in the SENP2 knockouts further leads to the proper formation of the heart structures, including atrioventricular cushion and myocardium. SUMO2 and SUMO3 modifications regulate placentation and organogenesis mediated by SENP2.

Keywords: SENP; SUMO; SUMOylation; cardiovascular deformity; mouse genetics; placental insufficiency; protease.

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Conflict of interest statement

The authors declare no potential conflict of interest.

Figures

Figure 1
Figure 1
Secondary defects in heart formation caused by placental deficiencies in the SENP2 knockout. Gross morphological evaluation of the wild type (A, C) and SENP2−/− (B, D), embryos at E11.5 (A‐B) and 12.5 (C‐D). Histology shows the atrioventricular (AV) cushion (E‐F; asterisks) and myocardium (G‐H) defective in the SENP2 knockout. Scale bars, 3 mm (A‐D); 100 μm (E‐H). SENP2, SUMO‐specific protease 2
Figure 2
Figure 2
SENP2 genetically interacts with SUMO2 and SUMO2 during the formation of three major trophoblast layers. Histology examines the placentas of SENP2+/+ (A, A′) and SENP2+/+; SUMO2+/− (B, B′), SENP2+/+; SUMO3−/− (C, C′), SENP2−/− (D, D′), SENP2−/−; SUMO2+/− (E, E′) and SENP2−/−; SUMO3−/− (F, F′) in transverse sections at E10.5. Labyrinth (L), spongiotrophoblast (S) and trophoblast giant cell (G) layers were defined by blue, red and green broken lines, respectively. Scale bars, 200 μm (A‐F, A′‐F′). SENP, SUMO‐specific protease; SUMO, small ubiquitin‐related modifier
Figure 3
Figure 3
Alleviation of heart deformities caused by SENP2 deficiency. (A‐C) Gross morphological evaluation of the SENP2+/+; SUMO2+/− (A), SENP2+/−; SUMO2+/− (B) and SENP2−/−; SUMO2+/− (C) embryos at E12.5. Histology shows embryo homozygous for SENP2 and heterozygous for SUMO2 (F, I, L) exhibiting the proper formation of the atrioventricular (AV) cushion (D‐I) and myocardium (MC; D‐F, J‐L) comparable to the control (D‐E, G‐H, J‐K). Scale bars, 4 mm (A‐C); 200 μm (D‐L). SENP, SUMO‐specific protease; SUMO, small ubiquitin‐related modifier
Figure 4
Figure 4
The loss of SUMO3 alleviates heart deformities associated with the SENP2 ablation. (A‐C) Gross morphological evaluation of the SENP2+/+; SUMO3−/− (A, M), SENP2+/−; SUMO3−/− (B, P) and SENP2−/−; SUMO3−/− (C, O) embryos at E12.5 (A‐C) and 13.5 (M‐O). Histology analysis reveals that the SENP2 and SUMO3 double knockout (F, I, L) displays the proper formation of the atrioventricular (AV) cushion (D‐I) and myocardium (MC; D‐F, J‐L) comparable to the control (D‐E, G‐H, J‐K). Scale bars, 4 mm (A‐C, M‐O); 200 μm (D‐F); 100 μm (G‐L). SENP, SUMO‐specific protease; SUMO, small ubiquitin‐related modifier
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