Center for Nuclear Receptors and Cell Signaling, University of Houston, Houston, TX 77204, USA.
Proc Natl Acad Sci U S A. 2010 Jul 6;107(27):12305-10. doi: 10.1073/pnas.1006162107. Epub 2010 Jun 21.
In the past year, two members of the nuclear receptor family, liver X receptor beta (LXRbeta) and thyroid hormone receptor alpha (TRalpha), have been found to be essential for correct migration of neurons in the developing cortex in mouse embryos. TRalpha and LXRbeta bind to identical response elements on DNA and sometimes regulate the same genes. The reason for the migration defect in the LXRbeta(-/-) mouse and the possibility that TRalpha may be involved are the subjects of the present study. At E15.5, expression of reelin and VLDLR was similar but expression of apolipoprotein E receptor 2 (ApoER2) (the reelin receptor) was much lower in LXRbeta(-/-) than in WT mice. Knockout of ApoER2 is known to lead to abnormal cortical lamination. Surprisingly, by postnatal day 14 (P14), no morphological abnormalities were detectable in the cortex of LXRbeta(-/-) mice and ApoER2 expression was much stronger than in WT controls. Thus, a postnatal mechanism leads to increase in ApoER2 expression by P14. TRalpha also regulates ApoER2. In both WT and LXRbeta(-/-) mice, expression of TRalpha was high at postnatal day 2. By P14 it was reduced to low levels in WT mice but was still abundantly expressed in the cortex of LXRbeta(-/-) mice. Based on the present data we hypothesize that reduction in the level of ApoER2 is the reason for the retarded migration of later-born neurons in LXRbeta(-/-) mice but that as thyroid hormone (TH) increases after birth the neurons do find their correct place in the cortex.
在过去的一年中，两种核受体家族成员——肝 X 受体β（LXRβ）和甲状腺激素受体α（TRα）——被发现对于小鼠胚胎发育中皮质神经元的正确迁移至关重要。TRα 和 LXRβ与 DNA 上相同的反应元件结合，有时会调节相同的基因。LXRβ（-/-）小鼠中迁移缺陷的原因以及 TRα 可能参与的原因是本研究的主题。在 E15.5 时，reelin 和 VLDLR 的表达相似，但 LXRβ（-/-）小鼠中 apoer2（reelin 受体）的表达比 WT 小鼠低得多。已知 apoer2 的敲除会导致皮质层状结构异常。令人惊讶的是，到出生后第 14 天（P14），LXRβ（-/-）小鼠的皮质中没有可检测到的形态异常，并且 apoer2 的表达比 WT 对照强得多。因此，一种出生后的机制导致 P14 时 apoer2 表达增加。TRα 也调节 apoer2。在 WT 和 LXRβ（-/-）小鼠中，TRα 的表达在出生后第 2 天很高。到 P14 时，它在 WT 小鼠中降低到低水平，但在 LXRβ（-/-）小鼠的皮质中仍大量表达。基于目前的数据，我们假设 apoer2 水平的降低是 LXRβ（-/-）小鼠中晚期神经元迁移延迟的原因，但由于甲状腺激素（TH）在出生后增加，神经元确实在皮质中找到了它们的正确位置。
