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And Thyroid Hormone Receptor Α in Brain Cortical Layering Correction NEUROSCIENCE Correction for “Liver X receptor β and thyroid hormone re- ceptor α in brain cortical layering,” by Xin-jie Tan, Xiao-tang Fan, Hyun-jin Kim, Ryan Butler, Paul Webb, Margaret Warner, and Jan-Åke Gustafsson, which appeared in issue 27, July 6, 2010, of Proc Natl Acad Sci USA (107:12305–12310; first pub- lished June 21, 2010; 10.1073/pnas.1006162107). The authors note that Fig. 1 appeared incorrectly. The cor- rected figure and its legend appear below. E6316–E6317 | PNAS | October 11, 2016 | vol. 113 | no. 41 www.pnas.org Downloaded by guest on October 2, 2021 CORRECTION Fig. 1. Morphological alteration of embryonic and early postnatal cortex in LXRβ−/− mice. (A–I) Sagittal sections of the E15.5 neocortex and coronal sections − − of P2 and P14 stained with cresyl violet. (A and B) At E15.5, the CP is thinner and density of neurons in the IZ is higher in LXRβ / mice (B) than in WT controls − − − − (A). (C and D) At P2, the layers II/III in LXRβ / mice (D) are thinner than in WT controls (C) and the neuronal density in layers IV and V of LXRβ / mice (D)is − − higher than that of WT controls (C). (E and F) No overall morphological difference can be observed in the cortex in LXRβ / mice (F) compared with WT controls (E) at P14. (A–F) There is no visible difference in the MZ, SVZ, and VZ at E15.5 (A and B) and layer I at P2 (C and D) or P14 (E and F) between WT and LXRβ−/− mice. (G and I) The thickness of cortical layers at E15.5 (G)(*P = 0.002 for CP; **P = 0.012 for IZ of LXRβ−/− mice compared with WT controls, by Student’s t test), and the thickness of layers II/III at P2 and P14 (I)(*P = 0.01 at P2 for LXRβ−/− mice compared with WT controls). (H) The density of cells/0.1 mm2. − − In LXRβ / mouse brain, there is a significant increase in the IZ at E15.5 (*P = 0.001), layer IV (**P = 0.032), and V (***P = 0.008) at P2. All of the results were expressed as mean ± SD. Three brains were used for each genotype. (Scale bars: A–F,50μm.) www.pnas.org/cgi/doi/10.1073/pnas.1614988113 PNAS | October 11, 2016 | vol. 113 | no. 41 | E6317 Downloaded by guest on October 2, 2021 Liver X receptor β and thyroid hormone receptor α in brain cortical layering Xin-jie Tana, Xiao-tang Fanb, Hyun-jin Kima, Ryan Butlera, Paul Webbc, Margaret Warnera, and Jan-Åke Gustafssona,d,1 aCenter for Nuclear Receptors and Cell Signaling, University of Houston, Houston, TX 77204; bDepartment of Neurobiology, Third Military Medical University, Chongqing 400038, China; cMethodist Hospital Research Institute, Houston, TX 77030; and dDivision of Medical Nutrition, Department of Biosciences and Nutrition, Karolinska Institute, Novum, 141 86 Stockholm, Sweden Contributed by Jan-Åke Gustafsson, May 4, 2010 (sent for review February 27, 2010) − − In the past year, two members of the nuclear receptor family, liver Cortical abnormalities observed with LXRβ / mice are strik- X receptor β (LXRβ) and thyroid hormone receptor α (TRα), have ingly similar to defects produced by mutations of apolipoprotein E been found to be essential for correct migration of neurons in the receptor 2 (ApoER2) (11), originally termed the LDL receptor- developing cortex in mouse embryos. TRα and LXRβ bind to iden- related protein CD91 (12). ApoER2 and its ligand reelin are es- tical response elements on DNA and sometimes regulate the same sential for migration of developing cortical neurons to find their − − genes. The reason for the migration defect in the LXRβ / mouse place in the correct layer of the cortex (11, 13). Reelin is normal in − − and the possibility that TRα may be involved are the subjects of LXRβ / mice (9), but the fact that there are defects in neuronal the present study. At E15.5, expression of reelin and VLDLR was migration in the cortex raises the question of whether there may similar but expression of apolipoprotein E receptor 2 (ApoER2) (the be defects in ApoER2. − − reelin receptor) was much lower in LXRβ / than in WT mice. Many members of the nuclear hormone receptor family play Knockout of ApoER2 is known to lead to abnormal cortical lami- important roles in brain development. Thyroid hormone (TH) nation. Surprisingly, by postnatal day 14 (P14), no morphological regulates brain development and hypothyroidism can lead to − − abnormalities were detectable in the cortex of LXRβ / mice and mental retardation, anxiety, and even psychosis (14, 15). TH ApoER2 expression was much stronger than in WT controls. Thus, signaling is mediated by two closely related thyroid hormone a postnatal mechanism leads to increase in ApoER2 expression by receptors (TRs), with the TRα subtype strongly expressed in the − − P14. TRα also regulates ApoER2. In both WT and LXRβ / mice, brain (16). Like LXRs, the TRs are mostly localized in nuclei expression of TRα was high at postnatal day 2. By P14 it was re- and associate with DNA in the presence and absence of their duced to low levels in WT mice but was still abundantly expressed cognate ligand. TH, whose circulating levels increase sharply − − in the cortex of LXRβ / mice. Based on the present data we hy- after birth, regulates gene expression by altering receptor con- pothesize that reduction in the level of ApoER2 is the reason for formation and changing the complement of coregulators that are − − the retarded migration of later-born neurons in LXRβ / mice but recruited to TR on promoters of target genes (17–19). Recent that as thyroid hormone (TH) increases after birth the neurons do evidence suggests that TRs can also relocate to the cytoplasm, find their correct place in the cortex. where they may trigger rapid second messenger signaling events (20). The role of cytoplasmic TRs is not clear. apolipoprotein E receptor 2 | cerebral cortex | development | embryo LXRs bind to the same response element on DNA as TRs and sometimes regulate the same genes (21–23). The defects in − − iver X receptor (LXR) is a subfamily of the nuclear receptor cholesterol homeostasis seen in the livers of LXRα / mice are Lfamily of transcription factors. The two members of this not compensated for by TRs (24), but interactions of LXRs and subfamily are LXRα (1), which plays a key role in cholesterol TRs in the CNS have not been investigated. homeostasis and LXRβ (2), which has irreplaceable functions in In the present study, we have analyzed the architecture of the β−/− the central nervous system (3–6). cerebral cortex in embryonic and neonatal LXR mice. Re- We have previously shown that LXRβ regulates brain choles- markably, morphological abnormalities of the cortex seen at terol levels and that LXRβ expression is essential for maintenance E15.5 are normalized between postnatal day 2 (P2) and postnatal of motor neurons in the spinal cord and dopaminergic neurons in day 14 (P14). We now present evidence for the role of ApoER2 and TR in the abnormalities and reparation of the defects and the substantia nigra, suggesting that there are important roles for propose that TRα compensates for the lack of LXRβ in cortical LXR action in brain development and, possibly, also in neuro- development. logical disease (7, 8). LXRβ is widely expressed in mouse brain at later embryonic stages and is localized in the upper layers of the Results cerebral cortex in normal postnatal mice (9). Our analysis of brain Abnormal Cortical Layers in LXRβ−/− Mice at a Late Embryonic Stage −/− development in LXRβ mice revealed smaller brain size, which and Early Postnatal Stages. The laminated structure of the cerebral was caused by a reduction in the number of neurons in superficial cortex was examined at later embryonic and early postnatal stages − − cortical layers (9). Mammalian corticogenesis involves layering of and a comparison was made between LXRβ / mice and WT neurons in an “inside-out” fashion, with earliest generated neurons controls with cresyl violet Nissl staining. At E15.5, the cortical plate − − positioned in the deepest layers and later generated neurons mi- (CP) appeared thinner in the LXRβ / mice than in WT controls, grating beyond previously established layers to adopt progressively whereas the intermediate zone (IZ) was thicker in the mutant mice more superficial levels (9, 10). This process is essential for cortical than in WT controls (Fig. 1 A, B,andG). There was no overall NEUROSCIENCE structure and establishment of correct neural connections. We − − have shown that the defect in cortical development in LXRβ / mice is a direct consequence of an inability of later-born neurons Author contributions: X.T., M.W., and J.-Å.G. designed research; X.T., X.F., H.K., R.B., and fi M.W. performed research; X.T., P.W., M.W., and J.-Å.G. analyzed data; and X.T., M.W., to migrate to super cial layers and that this, in turn, is a conse- and J.-Å.G. wrote the paper. quence of abnormalities in vertical processes of radial glial cells The authors declare no conflict of interest. β along which migrating neurons travel (9). Thus, LXR plays 1To whom correspondence should be addressed. E-mail: [email protected]. fi aspeci c role in cortex lamination and is essential for radial mi- This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. gration of later-generated neocortical neurons in embryonic mice. 1073/pnas.1006162107/-/DCSupplemental. www.pnas.org/cgi/doi/10.1073/pnas.1006162107 PNAS | July 6, 2010 | vol. 107 | no. 27 | 12305–12310 difference in the appearance or thickness of the marginal zone (MZ), subventricular zone (SVZ), or ventricular zone (VZ).
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