A genomic atlas of human adrenal and gonad development

Ignacio Del Valle,Rahul Parnaik,Martino Barenco,Dianne Gerrelli,Federica Buonocore,Sonia Shah,Mike Hubank,Andrew J Duncan,Lin Lin,John C Achermann

doi:10.12688/wellcomeopenres.11253.1

Abstract

Background: In humans, the adrenal glands and gonads undergo distinct biological events between 6-10 weeks post conception (wpc), such as testis determination, the onset of steroidogenesis and primordial germ cell development. However, relatively little is currently known about the genetic mechanisms underlying these processes. We therefore aimed to generate a detailed genomic atlas of adrenal and gonad development across these critical stages of human embryonic and fetal development.Methods: RNA was extracted from 53 tissue samples between 6-10 wpc (adrenal, testis, ovary and control). Affymetrix array analysis was performed and differential gene expression was analysed using Bioconductor. A mathematical model was constructed to investigate time-series changes across the dataset. Pathway analysis was performed using ClueGo and cellular localisation of novel factors confirmed using immunohistochemistry.Results: Using this approach, we have identified novel components of adrenal development (e.g.ASB4,NPR3) and confirmed the role ofSRYas the main human testis-determining gene. By mathematical modelling time-series data we have found new genes up-regulated withSOX9in the testis (e.g.CITED1), which may represent components of the testis development pathway. We have shown that testicular steroidogenesis has a distinct onset at around 8 wpc and identified potential novel components in adrenal and testicular steroidogenesis (e.g.MGARP,FOXO4,MAP3K15,GRAMD1B,RMND2), as well as testis biomarkers (e.g.SCUBE1). We have also shown that the developing human ovary expresses distinct subsets of genes (e.g.OR10G9,OR4D5), but enrichment for established biological pathways is limited.Conclusion: This genomic atlas is revealing important novel aspects of human development and new candidate genes for adrenal and reproductive disorders.

Highlights

The development of the adrenal gland and gonads are two of the most important embryological events, but relatively little is known about the exact mechanisms of these processes in humans.Development of these structures is closely linked as they arise from a shared region of intermediate mesoderm in early embryogenesis and subsequently have common biological processes, such as the ability to synthesise steroid hormones.The primordial adrenal gland arises as a distinct structure at around 28 days post-conception and undergoes rapid growth during late embryonic and early fetal life (Ishimoto & Jaffe, 2011)
Rather than using a correlative approach, we developed a mathematical model that could be used to capture subtle changes in our dataset more quantitatively. Using this approach, coupled with subsequent review of gene expression in different fetal and adult tissues, we have identified a small group of genes that are up-regulated with SOX9 in the testis (e.g., CITED1, ZNF280B, PRPS2)
We have shown by immunohistochemistry that there is clear upregulation of GRAMD1B in the cytoplasm of NR5A1positive steroidogenic cells with the onset of steroidogenesis in humans

Summary

Introduction

The development of the adrenal gland and gonads (testes, ovaries) are two of the most important embryological events, but relatively little is known about the exact mechanisms of these processes in humans.Development of these structures is closely linked as they arise from a shared region of intermediate mesoderm in early embryogenesis and subsequently have common biological processes, such as the ability to synthesise steroid hormones (see Figure 1 for an overview).The primordial adrenal gland arises as a distinct structure at around 28 days post-conception (dpc) and undergoes rapid growth during late embryonic and early fetal life (Ishimoto & Jaffe, 2011). The development of the adrenal gland and gonads (testes, ovaries) are two of the most important embryological events, but relatively little is known about the exact mechanisms of these processes in humans. Development of these structures is closely linked as they arise from a shared region of intermediate mesoderm in early embryogenesis and subsequently have common biological processes, such as the ability to synthesise steroid hormones (see Figure 1 for an overview). The adrenal glands and gonads undergo distinct biological events between 6-10 weeks post conception (wpc), such as testis determination, the onset of steroidogenesis and primordial germ cell development. Conclusion: This genomic atlas is revealing important novel aspects of human development and new candidate genes for adrenal and reproductive disorders

Objectives

Methods

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Discussion

Conclusion