PMID- 28688895
OWN - NLM
STAT- MEDLINE
DCOM- 20171012
LR  - 20181113
IS  - 1095-564X (Electronic)
IS  - 0012-1606 (Print)
IS  - 0012-1606 (Linking)
VI  - 429
IP  - 1
DP  - 2017 Sep 1
TI  - Differential requirement of SUFU in tissue development discovered in a 
      hypomorphic mouse model.
PG  - 132-146
LID - S0012-1606(17)30050-7 [pii]
LID - 10.1016/j.ydbio.2017.06.037 [doi]
AB  - Suppressor of Fused (SUFU) is an essential negative regulator of the Hedgehog 
      (HH) pathway and involved in GLI transcription factor regulation. Due to early 
      embryonic lethality of Sufu(-/-) mice, investigations of SUFU's role later in 
      development are limited to conditional, tissue-specific knockout models. In this 
      study we developed a mouse model (Sufu(Ex456(fl)/Ex456(fl))) with hypomorphic 
      features where embryos were viable up to E18.5, although with a spectrum of 
      developmental defects of varying severity, including polydactyly, exencephaly and 
      omphalocele. Development of certain tissues, like the skeleton, was more affected 
      than that of others such as skin, which remained largely normal. Interestingly, 
      no apparent changes in the dorso-ventral patterning of the neural tube at E9.0 
      could be seen. Thus, this model provides an opportunity to globally study SUFU's 
      molecular function in organogenesis beyond E9.5. Molecularly, 
      Sufu(Ex456(fl)/Ex456(fl)) embryos displayed aberrant mRNA splicing and 
      drastically reduced levels of Sufu wild-type mRNA and SUFU protein in all 
      tissues. As a consequence, at E9.5 the levels of all three different GLI proteins 
      were reduced. Interestingly, despite the reduction of GLI3 protein levels, the 
      critical ratio of the GLI3 full-length transcriptional activator versus GLI3 
      truncated repressor remained unchanged compared to wild-type embryos. This 
      suggests that the limited amount of SUFU protein present is sufficient for GLI 
      processing but not for stabilization. Our data demonstrate that tissue 
      development is differentially affected in response to the reduced SUFU levels, 
      providing novel insight regarding the requirements of different levels of SUFU 
      for proper organogenesis.
CI  - Copyright (c) 2017 Elsevier Inc. All rights reserved.
FAU - Hoelzl, Maria A
AU  - Hoelzl MA
AD  - Department of Biosciences and Nutrition, Karolinska Institutet, SE-141 83 
      Huddinge, Sweden. Electronic address: maria.holzl@ki.se.
FAU - Heby-Henricson, Karin
AU  - Heby-Henricson K
AD  - Department of Biosciences and Nutrition, Karolinska Institutet, SE-141 83 
      Huddinge, Sweden.
FAU - Gerling, Marco
AU  - Gerling M
AD  - Department of Biosciences and Nutrition, Karolinska Institutet, SE-141 83 
      Huddinge, Sweden.
FAU - Dias, Jose M
AU  - Dias JM
AD  - Department of Cell and Molecular Biology, Karolinska Institutet, SE-171 77 
      Stockholm, Sweden.
FAU - Kuiper, Raoul V
AU  - Kuiper RV
AD  - Department of Laboratory Medicine, Karolinska Institutet, SE-141 86 Huddinge, 
      Sweden.
FAU - Trunkle, Cornelius
AU  - Trunkle C
AD  - Department of Biosciences and Nutrition, Karolinska Institutet, SE-141 83 
      Huddinge, Sweden.
FAU - Bergstrom, Asa
AU  - Bergstrom A
AD  - Department of Biosciences and Nutrition, Karolinska Institutet, SE-141 83 
      Huddinge, Sweden.
FAU - Ericson, Johan
AU  - Ericson J
AD  - Department of Cell and Molecular Biology, Karolinska Institutet, SE-171 77 
      Stockholm, Sweden.
FAU - Toftgard, Rune
AU  - Toftgard R
AD  - Department of Biosciences and Nutrition, Karolinska Institutet, SE-141 83 
      Huddinge, Sweden.
FAU - Teglund, Stephan
AU  - Teglund S
AD  - Department of Biosciences and Nutrition, Karolinska Institutet, SE-141 83 
      Huddinge, Sweden. Electronic address: stephan.teglund@ki.se.
LA  - eng
GR  - P01 AR047898/AR/NIAMS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20170705
PL  - United States
TA  - Dev Biol
JT  - Developmental biology
JID - 0372762
RN  - 0 (Hedgehog Proteins)
RN  - 0 (RNA Splice Sites)
RN  - 0 (RNA, Messenger)
RN  - 0 (Repressor Proteins)
RN  - 0 (Sufu protein, mouse)
SB  - IM
MH  - Alleles
MH  - Animals
MH  - Body Patterning/genetics
MH  - Embryo, Mammalian/metabolism
MH  - Exons/genetics
MH  - Female
MH  - Gene Expression Regulation, Developmental
MH  - Hedgehog Proteins/metabolism
MH  - Homozygote
MH  - Male
MH  - Mice, Inbred BALB C
MH  - Mice, Inbred C57BL
MH  - Mice, Nude
MH  - Models, Animal
MH  - Neural Tube/embryology/metabolism
MH  - *Organogenesis/genetics
MH  - Point Mutation/genetics
MH  - RNA Splice Sites/genetics
MH  - RNA, Messenger/genetics/metabolism
MH  - Repressor Proteins/genetics/*metabolism
PMC - PMC5569906
MID - NIHMS893294
OTO - NOTNLM
OT  - Embryogenesis
OT  - GLI
OT  - Hedgehog pathway
OT  - Hypomorph
OT  - Skeletogenesis
OT  - Suppressor of Fused
EDAT- 2017/07/10 06:00
MHDA- 2017/10/13 06:00
PMCR- 2018/09/01
CRDT- 2017/07/10 06:00
PHST- 2017/01/27 00:00 [received]
PHST- 2017/06/30 00:00 [revised]
PHST- 2017/06/30 00:00 [accepted]
PHST- 2017/07/10 06:00 [pubmed]
PHST- 2017/10/13 06:00 [medline]
PHST- 2017/07/10 06:00 [entrez]
PHST- 2018/09/01 00:00 [pmc-release]
AID - S0012-1606(17)30050-7 [pii]
AID - 10.1016/j.ydbio.2017.06.037 [doi]
PST - ppublish
SO  - Dev Biol. 2017 Sep 1;429(1):132-146. doi: 10.1016/j.ydbio.2017.06.037. Epub 2017 
      Jul 5.