ESPE Abstracts

Background: The adrenal glands and gonads develop from an area of intermediate mesoderm between 6 and 10 weeks post conception (wpc) in humans. Elucidating the genomic components and pathways in these processes could reveal novel aspects of human developmental biology and new factors implicated in adrenal insufficiency and DSD.

Objective and hypotheses: To develop a unique genomic atlas of adrenal and gonad development during critical stages of human embryonic organogenesis.

Method: In collaboration with the Wellcome Trust-MRC Human Developmental Biology Resource, RNA was extracted from 58 tissue samples between 6 and 10 wpc (22 adrenal, 20 testis, 10 ovary, 6 control). Gene expression was determined using Affymetrix Exon 1.0 ST arrays, generating 1.5 million data points. Global differences in gene expression between tissues were elucidated using Bioconductor and Partek. A novel phenomenological mathematical model was developed to investigate time-series changes across the dataset. Data were validated with qRT-PCR and immunohistochemistry.

Results: The adrenal gland develops a specific genomic signature early in development with marked differential expression of known genes (e.g. CYP17A1, CYP11A1, STAR, MC2R) and novel genes (e.g. OSAP, MAP3K15, ASB4). In the developing testis, SRY was the differentially expressed Y-chromosome gene at 6 wpc. By modelling resultant SOX9 upregulation, several potential new testis development genes were identified (e.g. CITED1, ZNF280B). Known steroidogenic genes showed consistent upregulation around 8 wpc in the testis with a sigmoidal time-series pattern. By combining adrenal and testis datasets, several potential novel steroidogenic components were identified (e.g. GRAMD1B, SLC16A9). Ovarian genes were enriched for germ cell factors, olfactory receptors and NPY. Remarkably, the only transcription factor differentially expressed in adrenal, testis and ovary was SF-1/NR5A1.

Conclusion: A unique, highly-validated genomic atlas of human adrenal and gonad development has been generated. This resource is revealing novel pathways in human development and new candidate genes for adrenal and reproductive disorders.

Funding: JCA is a Wellcome Trust Senior Research Fellow in Clinical Science (098513). The human embryonic and fetal material was provided by the Joint MRC/Wellcome Trust grant number 099175/Z/12/Z Human Developmental Biology Resource (http://hdbr.org).