PMID- 36103394
OWN - NLM
STAT- MEDLINE
DCOM- 20221219
LR  - 20221221
IS  - 1557-8534 (Electronic)
IS  - 1547-3287 (Linking)
VI  - 31
IP  - 23-24
DP  - 2022 Dec
TI  - Suppressor of Fused Regulation of Hedgehog Signaling is Required for Proper 
      Astrocyte Differentiation.
PG  - 741-755
LID - 10.1089/scd.2022.0131 [doi]
AB  - Hedgehog signaling is essential for vertebrate development; however, less is 
      known about the negative regulators that influence this pathway. Using the mouse 
      P19 embryonal carcinoma cell model, suppressor of fused (SUFU), a negative 
      regulator of the Hedgehog (Hh) pathway, was investigated during retinoic acid 
      (RA)-induced neural differentiation. We found Hh signaling increased activity in 
      the early phase of differentiation, but was reduced during terminal 
      differentiation of neurons and astrocytes. This early increase in pathway 
      activity was required for neural differentiation; however, it alone was not 
      sufficient to induce neural lineages. SUFU, which regulates signaling at the 
      level of Gli, remained relatively unchanged during differentiation, but its loss 
      through CRISPR-Cas9 gene editing resulted in ectopic expression of Hh target 
      genes. Interestingly, these SUFU-deficient cells were unable to differentiate 
      toward neural lineages without RA, and when directed toward these lineages, they 
      showed delayed and decreased astrocyte differentiation; neuron differentiation 
      was unaffected. Ectopic activation of Hh target genes in SUFU-deficient cells 
      remained throughout RA-induced differentiation and this was accompanied by the 
      loss of Gli3, despite the presence of the Gli3 message. Thus, the study indicates 
      the proper timing and proportion of astrocyte differentiation requires SUFU, 
      likely acting through Gli3, to reduce Hh signaling during late-stage 
      differentiation.
FAU - Spice, Danielle M
AU  - Spice DM
AD  - Molecular Genetics Unit, Department of Biology, Western University, London, 
      Ontario, Canada.
AD  - Children's Health Research Institute, London, Ontario, Canada.
FAU - Dierolf, Joshua
AU  - Dierolf J
AUID- ORCID: 0000-0002-9342-6128
AD  - Department of Physiology and Pharmacology, Western University, London, Ontario, 
      Canada.
FAU - Kelly, Gregory M
AU  - Kelly GM
AUID- ORCID: 0000-0001-8612-364X
AD  - Molecular Genetics Unit, Department of Biology, Western University, London, 
      Ontario, Canada.
AD  - Children's Health Research Institute, London, Ontario, Canada.
AD  - Department of Physiology and Pharmacology, Western University, London, Ontario, 
      Canada.
LA  - eng
PT  - Journal Article
DEP - 20221013
PL  - United States
TA  - Stem Cells Dev
JT  - Stem cells and development
JID - 101197107
RN  - 0 (Hedgehog Proteins)
RN  - 0 (Sufu protein, mouse)
RN  - 0 (Repressor Proteins)
SB  - IM
MH  - Animals
MH  - Mice
MH  - Cell Differentiation/genetics
MH  - *Hedgehog Proteins/genetics
MH  - *Astrocytes/cytology
MH  - Signal Transduction
MH  - *Repressor Proteins/genetics
OTO - NOTNLM
OT  - astrocyte
OT  - differentiation
OT  - hedgehog
OT  - neuron
OT  - signaling
OT  - suppressor of fused
EDAT- 2022/09/15 06:00
MHDA- 2022/12/15 06:00
CRDT- 2022/09/14 13:24
PHST- 2022/09/15 06:00 [pubmed]
PHST- 2022/12/15 06:00 [medline]
PHST- 2022/09/14 13:24 [entrez]
AID - 10.1089/scd.2022.0131 [doi]
PST - ppublish
SO  - Stem Cells Dev. 2022 Dec;31(23-24):741-755. doi: 10.1089/scd.2022.0131. Epub 2022 
      Oct 13.