Review
Adrenocortical stem and progenitor cells: Unifying model of two proposed origins

https://doi.org/10.1016/j.mce.2010.11.012Get rights and content

Abstract

The origins of our understanding of the cellular and molecular mechanisms by which signaling pathways and downstream transcription factors coordinate the specification of adrenocortical cells within the adrenal gland have arisen from studies on the role of Sf1 in steroidogenesis and adrenal development initiated 20 years ago in the laboratory of Dr. Keith Parker.

Adrenocortical stem/progenitor cells have been predicted to be undifferentiated and quiescent cells that remain at the periphery of the cortex until needed to replenish the organ, at which time they undergo proliferation and terminal differentiation. Identification of these stem/progenitor cells has only recently been explored. Recent efforts have examined signaling molecules, including Wnt, Shh, and Dax1, which may coordinate intricate lineage and signaling relationships between the adrenal capsule (stem cell niche) and underlying cortex (progenitor cell pool) to maintain organ homeostasis in the adrenal gland.

Introduction

Dr. Keith Parker serendipitously became a pioneer in the molecular study of adrenal gland development and organogenesis when he cloned the gene for steroidogenic factor 1 (Sf1) as a transcriptional regulator of genes encoding steroidogenic enzymes (Luo et al., 1994). Dr. Parker's work occurred concurrently with studies emerging from the Morohashi laboratory on the steroidogenic transcription factor Ad4BP, which turned out to be identical to Sf1 (Hatano et al., 1996). Together, these studies surprisingly found that the adrenal glands did not form in mice with a genetically modified null allele of Sf1. Studies of Sf1 for over two decades have provided the molecular framework for the emerging field of adrenocortical stem and progenitor biology. The current research in the emerging field of adrenal organogenesis and data supporting the presence of adrenocortical stem/progenitor cells was recently reviewed (Kim et al., 2009). The current summary herein highlights a working model of adrenocortical stem/progenitor cell biology and the proposed stem cell niche and includes the emerging data supporting the hypothesis.

Section snippets

Adrenal anatomy

The adrenal glands are formed from two embryologically distinct tissues. The inner adrenal medulla is derived from neural crest cells of the neuroectoderm lineage and synthesizes catecholamines essential for the “fight-or-flight” response. The cortex is derived from cells of the intermediate mesoderm and is responsible for secretion of steroid hormones. The cortex is organized into three concentric zones, each with a discrete function, the synthesis and secretion of steroid hormones: (1) zona

Organogenesis

Adrenal gland organogenesis is orchestrated in discrete histological phases (Fig. 1; reviewed in Else and Hammer, 2005, Keegan and Hammer, 2002, Uotila, 1940). In the initial phase (4th week of gestation in humans, embryonic day (E) 9.0 in mice), the adrenogonadal primordium (AGP) is first distinguished and expresses the essential transcription factor SF1/Sf1 (Hatano et al., 1996, Luo et al., 1994). In the second phase (8th week gestation in humans, E10.5 in mice), the AGP separates into two

Evidence that the fetal cortex is the source of adrenocortical precursor cells

Sf1 expression is critical for proper adrenal organogenesis and is required for steroidogenic function in both the fetal and the adult cortex. As addressed by work of Zubair et al. (2006), the differential activity and regulation of Sf1 in the development and function of these two cell populations (fetal and adult cortex), is emerging as an essential mediator of adrenal gland organogenesis. These investigators identified a Fetal Adrenal Enhancer (FAdE) that directs Sf1 expression solely in the

Mediators of adrenal stem/progenitor cell maintenance, proliferation, and differentiation

As anticipated, a multitude of signaling pathways and transcription factors are emerging as critical mediators of adrenocortical growth and differentiation, including the regulation of adrenocortical stem/progenitor cells. The transcriptional mediators, β-catenin and Dax1, have drawn particular interest due to their role in human disease and their demonstrated regulation of Sf1 activity.

Conclusion

Since the inception of Keith Parker's groundbreaking work, much progress has been made to define the development and the signaling pathways involved in the maintenance and differentiation of the adrenal gland. In this review, data have been highlighted which support two different models for the source of adrenal stem/progenitor cells: the fetal adrenal and the adrenal capsule. Further studies are required to support or refute a unifying model whereby proposed transient cells arise from the

Acknowledgements

The authors thank Joanne H. Heaton for critical review and editing of this manuscript. This work was supported by National Institutes of Health (NIH) Grant DK062027 from National Institute of Diabetes and Digestive and Kidney Diseases (to G.D.H.) and Grant CA134606 from the National Cancer Institute (to G.D.H.); M.A.W was supported, by NIH Grant T32 DK07245 from theTraining Program in Endocrinology at the University of Michigan.

References (79)

  • X. Luo et al.

    A cell-specific nuclear receptor is essential for adrenal and gonadal development and sexual differentiation

    Cell

    (1994)
  • K. Morohashi et al.

    A common trans-acting factor, ad4-binding protein, to the promoters of steroidogenic p-450s

    J. Biol. Chem.

    (1992)
  • K.K. Niakan et al.

    Novel role for the orphan nuclear receptor dax1 in embryogenesis, different from steroidogenesis

    Mol. Genet. Metab.

    (2006)
  • A.N. Urs et al.

    Steroidogenic factor-1 is a sphingolipid binding protein

    Mol. Cell. Endocrinol.

    (2007)
  • K. Xie et al.

    Developmental biology informs cancer: the emerging role of the hedgehog signaling pathway in upper gastrointestinal cancers

    Cancer Cell

    (2003)
  • J.C. Achermann et al.

    A mutation in the gene encoding steroidogenic factor-1 causes xy sex reversal and adrenal failure in humans

    Nat. Genet.

    (1999)
  • P.S. Babu et al.

    Interaction between dax-1 and steroidogenic factor-1 in vivo: increased adrenal responsiveness to acth in the absence of dax-1

    Endocrinology

    (2002)
  • S.C. Bendall et al.

    Igf and fgf cooperatively establish the regulatory stem cell niche of pluripotent human cells in vitro

    Nature

    (2007)
  • A. Berthon et al.

    Constitutive beta-catenin activation induces adrenal hyperplasia and promotes adrenal cancer development

    Hum. Mol. Genet.

    (2010)
  • F. Beuschlein et al.

    Activin induces x-zone apoptosis that inhibits luteinizing hormone-dependent adrenocortical tumor formation in inhibin-deficient mice

    Mol. Cell. Biol.

    (2003)
  • L.A. Campbell et al.

    Decreased recognition of sumo-sensitive target genes following modification of sf-1 (nr5a1)

    Mol. Cell. Biol.

    (2008)
  • S. Ching et al.

    Targeted disruption of sonic hedgehog in the mouse adrenal leads to adrenocortical hypoplasia

    Genesis

    (2009)
  • S. Cui et al.

    Disrupted gonadogenesis and male-to-female sex reversal in pod1 knockout mice

    Development

    (2004)
  • T. Else

    Telomeres and telomerase in adrenocortical tissue maintenance, carcinogenesis, and aging

    J. Mol. Endocrinol.

    (2009)
  • T. Else et al.

    Evaluation of telomere length maintenance mechanisms in adrenocortical carcinoma

    J. Clin. Endocrinol. Metab.

    (2008)
  • T. Else et al.

    Tpp1/acd maintains genomic stability through a complex role in telomere protection

    Chromosome Res.

    (2007)
  • T.J. Giordano et al.

    Molecular classification and prognostication of adrenocortical tumors by transcriptome profiling

    Clin. Cancer Res.

    (2009)
  • B.M. Gummow et al.

    Reciprocal regulation of a glucocorticoid receptor-steroidogenic factor-1 transcription complex on the dax-1 promoter by glucocorticoids and adrenocorticotropic hormone in the adrenal cortex

    Mol. Endocrinol.

    (2006)
  • V.K. Han et al.

    Insulin-like growth factor-ii (igf-ii) messenger ribonucleic acid is expressed in steroidogenic cells of the developing ovine adrenal gland: Evidence of an autocrine/paracrine role for igf-ii

    Endocrinology

    (1992)
  • Y.G. Han et al.

    Hedgehog signaling and primary cilia are required for the formation of adult neural stem cells

    Nat. Neurosci.

    (2008)
  • O. Hatano et al.

    Identical origin of adrenal cortex and gonad revealed by expression profiles of ad4bp/sf-1

    Genes Cells

    (1996)
  • A. Hossain et al.

    Generation of two distinct functional isoforms of dosage-sensitive sex reversal-adrenal hypoplasia congenita-critical region on the x chromosome gene 1 (dax-1) by alternative splicing

    Mol. Endocrinol.

    (2004)
  • C.C. Huang et al.

    Progenitor cell expansion and organ size of mouse adrenal is regulated by sonic hedgehog

    Endocrinology

    (2010)
  • Y. Ikeda et al.

    Characterization of the mouse ftz-f1 gene, which encodes a key regulator of steroid hydroxylase gene expression

    Mol. Endocrinol.

    (1993)
  • Y. Ikeda et al.

    Developmental expression of mouse steroidogenic factor-1, an essential regulator of the steroid hydroxylases

    Mol. Endocrinol.

    (1994)
  • P.W. Ingham et al.

    Hedgehog signaling in animal development: Paradigms and principles

    Genes Dev.

    (2001)
  • K. Jeays-Ward et al.

    Endothelial and steroidogenic cell migration are regulated by wnt4 in the developing mammalian gonad

    Development

    (2003)
  • P. Jeyasuria et al.

    Cell-specific knockout of steroidogenic factor 1 reveals its essential roles in gonadal function

    Mol. Endocrinol.

    (2004)
  • P. Jimenez et al.

    Gata-6 is expressed in the human adrenal and regulates transcription of genes required for adrenal androgen biosynthesis

    Endocrinology

    (2003)
  • Cited by (56)

    • Primary cilia and Sonic hedgehog signaling in adrenal gland physiology and cancer

      2024, Current Opinion in Endocrine and Metabolic Research
    • Adrenal development

      2023, Genetic Steroid Disorders: Second Edition
    • Development and Function of the Adrenal Cortex and Medulla in the Fetus and Neonate

      2020, Maternal-Fetal and Neonatal Endocrinology: Physiology, Pathophysiology, and Clinical Management
    • Development and Function of the Adrenal Cortex and Medulla in the Fetus and Neonate

      2019, Maternal-Fetal and Neonatal Endocrinology: Physiology, Pathophysiology, and Clinical Management
    View all citing articles on Scopus
    View full text