Liver X receptor β and thyroid hormone receptor α in brain cortical layering

In the past year, two members of the nuclear receptor family, liver X receptor beta (LXR beta) and thyroid hormone receptor alpha (TR alpha), have been found to be essential for correct migration of neurons in the developing cortex in mouse embryos. TR alpha and LXR beta bind to identical response elements on DNA and sometimes regulate the same genes. The reason for the migration defect in the LXR beta(-/-) mouse and the possibility that TR alpha 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 LXR beta(-/-) 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 LXR beta(-/-) mice and ApoER2 expression was much stronger than in WT controls. Thus, a postnatal mechanism leads to increase in ApoER2 expression by P14. TRa also regulates ApoER2. In both WT and LXR beta(-/-) mice, expression of TRa 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 LXR beta(-/-) 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 LXR beta(-/-) mice but that as thyroid hormone (TH) increases after birth the neurons do find their correct place in the cortex.