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
• Publication Date: 2018-10-05T11:53:34Z
• Authors: Nicolás Santander; Carlos Lizama; Leandro Murgas; Sebastián Contreras; Alberto J. M. Martin; Paz Molina; Alonso Quiroz; Katherine Rivera; Francisca Salas-P...; Alejandro Godoy; Attilio Rigotti; Dolores Busso
• Keywords: CD36 Antigens; 0301 basic medicine; Neural Tube; Transcription, Genetic; 610; Lípidos -- Metabolismo; Lipoproteínas Metabolismo; Weaning; QH426-470; SR-B1; Gene Knockout Techniques; Mice; 03 medical and health sciences; Lípidos en la nutrición; 616; Genetics; Animals; Humans; Gene Regulatory Networks; RNA-Seq; Neural Tube Defects; Neural tube defects; Gene Expression Profiling; Androgen receptor; Phenotype; Gene expression; Medicina y salud; TP248.13-248.65; Biotechnology; Research Article

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.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.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.