Loss of testicular orphan receptor 4 impairs normal myelination in mouse forebrain.
Testicular orphan nuclear receptor 4 (TR4) has been suggested to play important roles in the development and functioning of the central nervous system (CNS). We find reduced myelination in TR4 knockout (TR4(-/-)) mice, which is particularly obvious in forebrains and in early developmental stages. Further analysis reveals that CC-1-positive (CC-1+) oligodendrocytes are decreased in TR4(-/-) forebrains. The O4+ signals are also reduced in TR4(-/-) forebrains when examined at postnatal d 7. However, the number and proliferation rate of platelet-derived growth factor receptor alpha-positive (PDGFalphaR+) oligodendrocyte precursor cells (OPCs) remain unaffected in these regions, suggesting that loss of TR4 interrupts oligodendrocyte differentiation. This is further supported by the observation that CC-1+ oligodendrocytes derived from 5-bromo-2'-deoxyuridine incorporating OPCs are significantly reduced in TR4(-/-) forebrains. We also find higher Jagged1 expression levels in axon fiber-enriched regions in TR4(-/-) forebrains, suggesting a more activated Notch signaling in these regions that correlates with previous reports showing that Notch activation inhibits oligodendrocyte differentiation. Together, our results suggest that TR4 is required for proper myelination in the CNS and is particularly important for oligodendrocyte differentiation and maturation in the forebrain regions. The altered Jagged1-Notch signaling in TR4(-/-) forebrain underlies a potential mechanism that contributes to the reduced myelination in the forebrain.
Zhang
Yanqing
Y
George Whipple Laboratory for Cancer Research, University of Rochester Medical Center, Rochester, New York 14642, USA.
Chen
Yei-Tsung
YT
Xie
Shaozhen
S
Wang
Liang
L
Lee
Yi-Fen
YF
Chang
Shu-Shi
SS
Chang
Chawnshang
C
D000818:Animals; D001253:Astrocytes / Q000166:cytology / Q000378:metabolism; D000071183:Autophagy-Related Proteins; D002135:Calcium-Binding Proteins / Q000378:metabolism; D002454:Cell Differentiation / Q000235:genetics; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000032:analysis; D000072100:Jagged-1 Protein; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D009186:Myelin Sheath / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism; D009836:Oligodendroglia / Q000737:chemistry / Q000166:cytology* / Q000378:metabolism; D016548:Prosencephalon / Q000166:cytology / Q000254:growth & development* / Q000378:metabolism; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000032:analysis; D051880:Receptors, Notch / Q000378:metabolism; D011987:Receptors, Steroid / Q000235:genetics / Q000502:physiology*; D011988:Receptors, Thyroid Hormone / Q000235:genetics / Q000502:physiology*; D000072099:Serrate-Jagged Proteins; D015398:Signal Transduction; D013737:Testis / Q000378:metabolism
D000071183:Autophagy-Related Proteins; D002135:Calcium-Binding Proteins; D036341:Intercellular Signaling Peptides and Proteins; D047908:Intracellular Signaling Peptides and Proteins; C000606274:Jag1 protein, mouse; D000072100:Jagged-1 Protein; D008565:Membrane Proteins; C490514:Nr2c2 protein, mouse; C428743:Rb1cc1 protein, mouse; D051880:Receptors, Notch; D011987:Receptors, Steroid; D011988:Receptors, Thyroid Hormone; D000072099:Serrate-Jagged Proteins; D020796:Receptor, Platelet-Derived Growth Factor alpha