BACKGROUND: The high-density lipoprotein receptor SR-B1 mediates cellular uptake
of several lipid species, including cholesterol and vitamin E. During early
mouse development, SR-B1 is located in the maternal-fetal interface, where it
facilitates vitamin E transport towards the embryo. Consequently, mouse embryos
lacking SR-B1 are vitamin E-deficient, and around half of them fail to close the
neural tube and show cephalic neural tube defects (NTD). Here, we used
transcriptomic profiling to identify the molecular determinants of this
phenotypic difference between SR-B1 deficient embryos with normal morphology or
with NTD.
RESULTS: We used RNA-Seq to compare the transcriptomic profile of three groups
of embryos retrieved from SR-B1 heterozygous intercrosses: wild-type E9.5
embryos (WT), embryos lacking SR-B1 that are morphologically normal, without NTD
(KO-N) and SR-B1 deficient embryos with this defect (KO-NTD). We identified over
1000 differentially expressed genes: down-regulated genes in KO-NTD embryos were
enriched for functions associated to neural development, while up-regulated
genes in KO-NTD embryos were enriched for functions related to lipid metabolism.
Feeding pregnant dams a vitamin E-enriched diet, which prevents NTD in SR-B1 KO
embryos, resulted in mRNA levels for those differentially expressed genes that
were more similar to KO-N than to KO-NTD embryos. We used gene regulatory
network analysis to identify putative transcriptional regulators driving the
different embryonic expression profiles, and identified a regulatory circuit
controlled by the androgen receptor that may contribute to this dichotomous
expression profile in SR-B1 embryos. Supporting this possibility, the expression
level of the androgen receptor correlated strongly with the expression of
several genes involved in neural development and lipid metabolism.
CONCLUSIONS: Our analysis shows that normal and defective embryos lacking SR-B1
have divergent expression profiles, explained by a defined set of transcription
factors that may explain their divergent phenotype. We propose that distinct
expression profiles may be relevant during early development to support
embryonic nutrition and neural tube closure.
