CGB - Universidad Mayor

05 octubre 2018

Transcriptional profiling of embryos lacking the lipoprotein receptor SR-B1 reveals a regulatory circuit governing a neurodevelopmental or metabolic decision during neural tube closure.

DOI : 10.1186/s12864-018-5110-2


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.

Investigadores Participantes del Centro



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