Diverse Functions of Hedgehog Signaling in Formation and Physiology of Steroidogenic Organs

doi:10.1002/mrd.21174

Mol Reprod Dev. Author manuscript; available in PMC 2012 July 19.

Published in final edited form as:

Mol Reprod Dev. 2010 June; 77(6): 489–496.

doi: 10.1002/mrd.21174

PMCID: PMC3400108

NIHMSID: NIHMS389469

Diverse Functions of Hedgehog Signaling in Formation and Physiology of Steroidogenic Organs

CHEN-CHE JEFF HUANG and HUMPHREY HUNG-CHANG YAO^*

Department of Veterinary Biosciences, University of Illinois, Urbana, Illinois

^*Corresponding author: Department of Veterinary Biosciences, University of Illinois, 3806 VMBSB, 2001 South Lincoln Avenue, Urbana, IL 61802. Email: hhyao/at/illinois.edu

The publisher's final edited version of this article is available at Mol Reprod Dev

See other articles in PMC that cite the published article.

SUMMARY

Adrenal, testis, and ovary are steroidogenic organs derived from a common primordium that consists of steroidogenic factor 1 (SF1)-positive precursor cells. SF1 not only defines the steroidogenic lineages in these organs but also controls their differentiation. Recent evidence implicates the Hedgehog (Hh) signaling pathway as a downstream regulator of SF1 in the appearance of steroidogenic cells in these organs. The Hh signaling pathway serves as a common crosstalk component, yet has evolved diverse functions in the expansion and differentiation of the steroidogenic cells in a tissue-specific manner. The purpose of this review is to compare and contrast the different roles of Hh signaling in these three organs during development.

INTRODUCTION

Adrenals and gonads (ovaries and testes) are the major sources of steroids essential for energy and salt homeostasis, immune functions, and reproduction. These organs share not only the ability to produce steroids, but also a common primordium when they first arise in embryos. In the mouse embryo around 9.5 days postcoitum (dpc), the adrenogonadal primordium forms as a result of proliferation of the coelomic epithelium that cover the urogenital ridge (Luo et al., 1994; Keegan and Hammer, 2002). Cells in the adrenogonadal primordium become distinguishable from other somatic cells as a result of the expression of the orphan nuclear receptor steroidogenic factor1 [Sf1, also known as Nr5a1, Ad4BP, or Ftzf1 (OMIM 184757)]. SF1 marks the steroidogenic precursors, which later become adrenal cortex and somatic cells in the future gonads (Fig. 1). SF1 is essential for the formation of the adrenals and gonads and development of pituitary gonadotrophs and ventromedial hypothalamic neurons (Rice et al., 1991; Luo et al., 1994; Ikeda et al., 1995; Shinoda et al., 1995). Between 10–11 dpc, via an unknown mechanism, the SF1-positive cells in the adrenogonadal primordium separate into two populations, which eventually differentiate into the adrenal primordium and gonadal primordium, respectively (Fig. 1).

Figure 1

Developmental timeline of SF1-positive cell lineages in the mouse fetal adrenal, testis, and ovary. At around 9 dpc, SF1-positive precursor cells start to appear in the adrenogonadal primordium. The adrenogonadal primordium separates into adrenal primordium (more ...)

In the developing adrenal primordium, SF1-expressing cells serve as the foundation for the fetal adrenocortex (Luo et al., 1994). Lineage tracing experiments suggest that the SF1-expressing fetal cortical cells also contribute to the adult adrenocortex (Zubair et al., 2008). The adrenal primordium is later encapsulated by the mesenchymal capsular cells, which is thought to provide stem/progenitor cells in adult or regenerating adrenal (Kim and Hammer, 2007; Kim et al., 2009). In the absence of Sf1, the adrenal primordium forms initially but then degenerates via programmed cell death, leading to adrenal agenesis at birth (Luo et al., 1994; Sadovsky et al., 1995).

Once separated from the adrenal primordium, the gonadal primordium undergoes dimorphic differentiation based on the genetic make-up of the embryos. In the XY embryo, a subset of the SF1-positive cells in the gonadal primordium starts to express the testis-determining gene Sry (Sex-determining region of the Y chromosome) and becomes Sertoli cells. SF1 participates in the establishment of Sertoli cells by regulating the expression of Sry, Sox9, and anti-Mullerian hormone (Amh) (Shen et al., 1994; Giuili et al., 1997; Sekido and Lovell-Badge, 2009). Sertoli cells then produce paracrine factors that induce differentiation of SF1-positive/SRY-negative Leydig cells outside the testis cords (Fig. 1). In the Leydig cells, SF1 controls the transcription of insulin-like growth factor 3 (Insl3) as well as various enzymes involved in steroidogenesis (Morohashi and Omura, 1996; Zimmermann et al., 1998; Cui et al., 2004; Park et al., 2007). In the male, testicular decent requires Leydig cell-derived Insl3, expression of which ould be regulated by androgen (Nef and Parada, 1999; Brokken et al., 2009; Tremblay et al., 2009).

In the XX mouse embryo that lacks the Sry gene, transcription and translation of SF1 decrease dramatically at 13.5 dpc, soon after the male and female gonads become morphologically different. SF1 level remains low in somatic cells of the fetal ovary but its expression rises again at the onset of folliculogenesis around the time of birth (Ikeda et al., 1994). SF1 is critical for granulosa cell development as granulosa cell-specific SF1 knockout females lack ovarian expression of SF1 target genes, resulting in decreased follicle numbers and infertility (Pelusi et al., 2008).

The presence of steroidogenic cells and their shared origin in adrenals and gonads raise the possibility that a common regulatory mechanism is present for the establishment of these steroidogenic cell lineages. In this review, we focus on the involvement of the Hh signaling, a conserved pathway in organogenesis among many species, in adrenal and gonadal development. We discuss recent findings on how this signaling pathway controls the growth and differentiation of the adrenocortex, testis, and ovary via a tissue-specific crosstalk among the SF1-positive cells.

COMPONENTS OF THE Hh SIGNALING PATHWAY

The Hh ligands are secreted proteins involved in many aspects of embryonic organ development and tumorigenesis in adult animals. Detailed information on the Hh pathway in mammals can be found in other reviews (Varjosalo and Taipale, 2008; Kasper et al., 2009) and only a general overview is provided here. In mammals, three Hh orthologs have been identified: Desert hedgehog (Dhh), Indian hedgehog (Ihh), and Sonic hedgehog (Shh). Although these three Hh genes have diverse expression patterns and functions, they are thought to induce a common signal transduction pathway in the target cells. Hh proteins bind to a receptor complex consisting of Patched family receptors (PTCH1 and PTCH2) and Smoothened (SMO) on the membrane. PTCH1 and PTCH2 have similar ligands binding affinity but their expression patterns are not fully overlapped (Carpenter et al., 1998). Hh-receiving cells are enriched with cilia where PTCH inhibits SMO activity by preventing its accumulation within cilia (Rohatgi et al., 2007). Binding of Hh to PTCH1 releases the inhibitory effect of PTCH1 on SMO, therefore allowing SMO to activate the downstream signaling components that involves transcription factors GLI1, GLI2, and GLI3 (Ingham and McMahon, 2001; Chari and McDonnell, 2007). In the absence of Hh, GLI2 and GLI3 are targeted for proteasomal processing (Sheng et al., 2006; Tempe et al., 2006; Wang and Li, 2006). The processed GLI2 and GLI3 serve as repressors that inhibit target gene transcription. In the presence of Hh, activated SMO inhibits proteolysis of GLI2 and GLI3, leading to the production of full-length transcriptional activator forms of these proteins. GLI1, on the other hand, contains only the activation domain and acts solely as a transcriptional activator (Dai et al., 1999). Although Hh ligands probably act through a common pathway, they elicit different effects in the tissue-specific manner, probably due to interaction with other signaling pathways (McMahon et al., 2003).

Hh SIGNALING IN THE FETAL ADRENAL

In the fetal mouse adrenal, Shh is the only Hh ligand present and its expression is restricted to SF1-positive adrenocortical cells underneath the adrenal capsule (Bitgood and McMahon, 1995; Kim et al., 2009). On the other hand, Ptch1, Gli1, and Gli2 expressions are found in the adrenal capsule, which is negative for SF1 (Ching and Vilain, 2009; King et al., 2009; Huang et al., 2010). We and others develop a conditional knockout mouse model that Shh is inactivated specifically in the SF1-positive adrenocortical cells (Ching and Vilain, 2009; King et al., 2009; Huang et al., 2010). Loss of Shh in the SF1-positive cells leads to severely stunted adrenal cortex and hypoplasia of the SF1-negative/Ptch1-positive adrenal capsule. The adrenal capsule and the underlying subcapsular cells are postulated to be the sources of progenitor/stem cells for the adrenocortex (Kim and Hammer, 2007). This concept is first raised from the result of cytological studies using the trypan blue dye. Trypan blue-labeled cells are restricted in the capsule right after the injection of the dye. Later on, the dye-labeled cells are found in the zona glomerulosa while the capsule becomes free of dye (Salmon and Zwemer, 1941). In adult rats, when the adrenal parenchyma is removed (a process called enucleation), a functional cortex is restored within 30 days, presumably due to regeneration of the remaining capsule and subcapsular cells (Skelton, 1959; Perrone et al., 1986). Using ³H-thymidine pulse-chase to trace proliferating cells, it was found that cortical cells migrate centripetally from outer to inner layers (Bertholet, 1980; Zajicek et al., 1986). An “escalator” hypothesis was therefore proposed such that the progenitor cells derived from the capsule migrate centripetally and become a part of adrenal cortex (Zwemer et al., 1938; Jones, 1948). The centripetal movement also occurs in the differentiated adrenocortical cells, which are aligned in columns (Ford and Young, 1963; Iannaccone et al., 2003). Using a genetic fate-mapping system that permanently marks Hh-responding Gli1-positive cells, we and others found that the Gli1-positive capsular cells indeed migrate centripetally and transform into SF1-positive adrenocortical cells (Ching and Vilain, 2009; King et al., 2009; Huang et al., 2010).

Shh derived from the SF1-positive adrenocortical cells apparently controls the expansion of progenitor cells in the capsule. This is based on the fact that both capsular thickness and the number of capsular cells are significantly reduced in the Shh knockout adrenal. We presented these results at the 2008 Endocrine Society Annual Meeting (ENDO) and the XII Adrenal Cortex Conference, and proposed the model that Shh from the SF1-positive cells regulates adrenal growth through proliferation of the progenitor cells in the capsule (Huang et al., 2008a,b). Despite significant underdevelopment, the Shh conditional knockout adrenocortex undergo proper zonation, indicating that Shh is dispensable for differentiation of adrenocortex. In addition, this observation also suggests two possible sources of adrenocortical cells: (1) the SF1-positive cells from the adrenal primordium, which forms the foundation of the organ and (2) SF1-negative capsular cells, which contribute to further growth of the adrenocortex (Fig. 2). The lineage tracing experiment performed by the Morohashi group demonstrates that the adult adrenocortex could derive from not only the SF1-positive cells in the fetal adrenal but also from unknown cell populations that are negative for SF1 (Zubair et al., 2008).

Figure 2

Hh signaling in the fetal adrenal. The SF1-positive precursor cells in the cortex form the foundation of the fetal adrenal. These cells produce SHH, but are negative for downstream Hh components such as Gli1 and Ptch1. Adrenocortex-derived SHH acts on (more ...)

In addition to Shh, Gli3 is another gene in the Hh pathway that plays a role in adrenal development. Gli3 mutant mice display a wide range of developmental abnormalities including absence of adrenal glands (Bose et al., 2002). In humans, Pallister–Hall syndrome (PHS) represents autosomal-dominant disorders associated with central polydactyly, imperforate anus, hypothalamic hamartoma, and other malformations (Clarren et al., 1980; Hall et al., 1980). A mutation in the Gli3 gene that results in a truncated form of GLI3 protein is found in some human PHS patients with adrenal hypoplasia and kidney malformation (Kang et al., 1997). It remains to be determined if Gli3 belongs to a component of the Shh pathway in the adrenal.

Hh SIGNALING IN THE FETAL TESTIS

In the fetal mouse testis, Sertoli cells start to produce Dhh at 11.5 dpc via a coordinate action of SF1 and DAX1, right after the onset of testis differentiation (Bitgood and McMahon, 1995; Bitgood et al., 1996; Park et al., 2005). The Hh receptor Ptch1 is expressed in the interstitial compartment 24 hr after Dhh expression (Bitgood et al., 1996) and Gli1 and Gli2 expression mirror the pattern of Ptch1 (unpublished results). The downregulation of Ptch1 in Dhh null mutants indicates that Dhh could be the primary Hh ligand in action in fetal testes (Bitgood et al., 1996).

Inactivation of the Dhh gene in mice with the 129/Sv inbred background results in properly formed testes; however, these male are infertile, with a complete absence of mature sperm (Bitgood et al., 1996). Interestingly, when the Dhh null alleles are introduced to a mixed genetic background, severe testis dysgenesis phenotypes arise in the fetal testis, including apolar Sertoli cells and anastomotic testis cords (Clark et al., 2000; Pierucci-Alves et al., 2001). In addition to testis cord dysgenesis, both Dhh knockout male mouse and human patients with DHH mutations exhibit male pseudohermaphroditism with underdevelopment of internal male accessory organs and feminized external genitalia due to insufficient production of androgens (Umehara et al., 2000; Canto et al., 2004, 2005). It was later found that loss of Dhh leads to a decreased number of fetal Leydig cells, the major source of androgens (Yao et al., 2002). However, a few fetal Leydig cells remain in the Dhh knockout testis, suggesting that other pathways such as Pdgf could partially compensate for the loss of Dhh (Brennan et al., 2003). When fetal testes are cultured ex vivo with the general Hh inhibitor cyclopamine prior to the appearance of fetal Leydig cells, no fetal Leydig cells are detected (Yao and Capel, 2002; Yao et al., 2002). However, cyclopamine has no effects on fetal Leydig cells when they are already present in the testis (Yao and Capel, 2002; Yao et al., 2002). To investigate if the Hh pathway alone is sufficient to induce fetal Leydig cell differentiation, we activated the Hh pathway ectopically in SF1-positive cells in the fetal ovary, where the Hh pathway is normally silent. Fully differentiated fetal Leydig cells appear in the fetal ovary in response to Hh activation. These ectopic fetal Leydig cells in the ovary are functional, producing enough testosterone to masculinize the female embryos (Barsoum et al., 2009). The effects of Hh activation on the transformation of SF1-positive cells to fetal Leydig cells in the ovary is direct, as evident by the absence of Sertoli cells and other testicular factors. These results together indicate that (1) the Hh pathway is the primary facilitator of fetal Leydig cell differentiation and (2) the Hh pathway is responsible for initiation, rather than maintenance, of fetal Leydig cell differentiation.

DHH triggers fetal Leydig cell differentiation by upregulating Sf1 expression in the precursors of fetal Leydig cells (Yao et al., 2002; Barsoum and Yao, 2009). Ectopic activation of the Hh pathway in the fetal ovary also induces expression of SF1 (Barsoum et al., 2009). In humans, SF1 haploinsufficiency is associated with impaired Leydig cell function (Jameson, 2004). Haploinsufficiency of Sf1 in mouse embryos causes delayed expression of both Sertoli and Leydig cell markers such as Amh, Cyp11a1, and Cyp17 (Park et al., 2005). Loss of one Sf1 allele in the Dhh knockout background (Sf1^+/−;Dhh^−/−) abolished the fetal Leydig cell population compared to the reduced fetal Leydig cell population in Sf1^+/+;Dhh^−/− males (Park et al., 2007). Several conserved Hedgehog responsive elements (HRE, TGGGTGGTC) are present in the mouse Sf1 promoter region, suggesting a direct role of the Hh signaling on Sf1 transcriptional regulation.

In summary, in the fetal testis, the SF1-positive precursor cells differentiate into at least two distinct somatic cell populations: DHH-producing Sertoli cells and DHH-responsive fetal Leydig cells. The main function of this paracrine crosstalk is to ensure the proper appearance of fetal Leydig cells and production of androgens (Fig. 3). In addition to Dhh, we have found that Shh mRNA is also expressed in the developing testis. However, contrary to the Dhh knockout, mice that lack Shh specifically in the SF1-positive cells in the testis are fertile, indicating that Shh alone is dispensable for testis development (unpublished results).

Figure 3

Hh signaling in the fetal testis. A subset of the SF1-positive precursor cells expresses SRY and become Sertoli cells. The SRY-positive Sertoli cells then produce paracrine factors such as DHH that act on fetal Leydig cell precursors in the testis interstitium. (more ...)

Hh SIGNALING IN THE OVARY

In the fetal mouse ovary, the Hh pathway is presumably inactive based on the fact that expression of Dhh, Ptch1, Gli1, and Gli2 is absent (Bitgood and McMahon, 1995; Yao et al., 2002). However, the Hh pathway appears to be activated in the adult mouse ovary. In situ hybridization results reveal the cellular sources of Dhh and Ihh as granulosa cells and the sources of Ptch1 and Gli1 as the adjacent theca cell compartment in mouse ovaries (Wijgerde et al., 2005; Russell et al., 2007). During preovulatory stages after superovulation induction, both Ptch1 and Gli1 in the theca cell compartment are gradually decreased along with the loss of expression of Ihh and Dhh in granulosa cells (Wijgerde et al., 2005). In vitro study shows that treatment of follicles with SHH increases proliferation of granulosa cells, while treatment with the Hh inhibitor cyclopamine increases progesterone production (Russell et al., 2007). Bovine theca cells express Ptch1 and Smo and treatment with SHH induces proliferation and androstenedione production in these cells in culture (Spicer et al., 2009). These data indicate a possible paracrine crosstalk between granulosa (source of Hh) and theca cells (Hh-responding cells) in steroidogenesis and cell proliferation (Fig. 4). Dhh knockout female mice have no obvious phenotypes and are fertile (Bitgood et al., 1996). In addition, inactivation of Shh in the SF1-positive cells in the ovary yields no ovarian phenotypes (unpublished results). Although other Hh ligands may compensate for the lack of Dhh or Shh in these cases, the exact role of the Hh pathway in ovarian development remains to be determined.

Figure 4

Hh signaling in the adult ovary. At the fetal stage, SF1 expression is high in precursor cells but is downregulated as these cells differentiate into ovarian cells. Components of the Hh pathways have not yet been defined at this stage. After birth, SF1 (more ...)

We have recently begun a study on roles of the Hh pathway in fetal ovary development. A distinct pattern of Gli1 and Gli2 expression begins to emerge at 14.5 dpc. Gli1 expression is absent in the ovary throughout fetal life; however, after birth, strings of Gli1-positive cells enter the ovarian medulla via the ovarian vasculature and later populate the stroma surrounding the follicle. In contrast to Gli1, Gli2 expression becomes detectable in the fetal ovary at 14.5 dpc in a subset of somatic cells (probably endothelial cells of the vasculature) surrounding the germ cell nest. These unpublished findings suggest that Gli1 and Gli2 play different roles in the ovary. We are in the process of defining their roles and investigating if these two Gli factors become active in an Hh-dependent or independent manner.

Expression of SHH, DHH, PTCH1, SMO, and GLI1 proteins is increased stepwise in benign, borderline, and malignant ovarian tumors (Chen et al., 2007; Bhattacharya et al., 2008). Inhibition of the Hh pathway by cyclopamine or Gli1 siRNA results in decreased cell proliferation of ovarian carcinoma cells (Chen et al., 2007). In addition, ectopic activation of the Hh pathway in mouse granulosa cells leads to infertility, reduced ovulation, and delayed luteinization (Ren et al., 2009). These observations indicate that aberrant activation of the Hh pathway may be responsible for ovarian abnormality and carcinogenesis.

CONCLUSION

The Hh family of proteins is one of the highly conserved paracrine/autocrine morphogens from metazoans to mammals. In the developing adrenals and gonads, evidence of paracrine crosstalk via the Hh pathway is emerging. The Hh ligands are produced by the earliest differentiated SF1-positive cells such as adrenocortical cells in the adrenal (Shh), Sertoli cells in the testis (Dhh), and granulosa cells in the ovary (Dhh and Ihh). These tissue-specific ligands then act upon Hh-responding cells located mainly in the mesenchyme, including capsular cells in the fetal adrenal, fetal Leydig cells in the testis, and theca cells in the adult ovary. Although their mode of paracrine action seems conserved, these Hh ligands induce tissue-specific cellular responses in these three organs. In the fetal adrenal, SHH controls adrenocortex expansion by inducing proliferation of the SF1-negative progenitor cells in the capsule. In the developing testis, DHH is the primary regulator that initiates fetal Leydig cell differentiation. In the adult ovary, multiple Hh ligands appear to be involved in steroidogenesis of the theca layer. It is interesting to note that most of the Hh-producing cells are SF1-positive and the Hh-receiving cells respond to the Hh ligand by upregulating SF1 expression. This suggests that Hh activation could be a universal mechanism for the induction of SF1 in certain cell lineages. More studies are needed to determine how certain cells in the adrenal and gonads acquire the ability to produce Hh and how a tissue-specific regulatory pattern is established. Furthermore, the role of the Hh pathway in adult adrenal and gonads require further investigation (Szczepny et al., 2009). A better understanding of the involvement of the Hh pathway will shed new light onto the normal process of organogenesis and the potential causes for neoplasia in these steroidogenic organs.

Acknowledgments

This study was supported by National Institute of Health (HD46861 to H.H.Y.) and Billie Field Memorial Scholarship (C.-C.J.H.). We also like to dedicate this review to our collaborator Dr. Keith Parker, who passed away on December 13, 2008.

Abbreviations


Amh	anti-Müllerian hormone

Hh	Hedgehog

Dhh	Desert

Ihh	Indian

Shh	Sonic

HRE	Hedgehog response element

Insl3	insulin-like growth factor 3

Ptch	Patched family of receptors

SF-1	steroidogenic factor 1

Smo	Smoothened receptor

Sry	sex-determining region of the Y chromosome

References

Barsoum IB, Yao HH. Fetal Leydig cells: Progenitor cell maintenance and differentiation. J Androl. 2009;31:11–15. [PMC free article] [PubMed]
Barsoum IB, Bingham NC, Parker KL, Jorgensen JS, Yao HH. Activation of the Hedgehog pathway in the mouse fetal ovary leads to ectopic appearance of fetal Leydig cells and female pseudohermaphroditism. Dev Biol. 2009;329:96–103. [PMC free article] [PubMed]
Bertholet JY. Proliferative activity and cell migration in the adrenal cortex of fetal and neonatal rats: An autoradiographic study. J Endocrinol. 1980;87:1–9. [PubMed]
Bhattacharya R, Kwon J, Ali B, Wang E, Patra S, Shridhar V, Mukherjee P. Role of hedgehog signaling in ovarian cancer. Clin Cancer Res. 2008;14:7659–7666. [PubMed]
Bitgood MJ, McMahon AP. Hedgehog and Bmp genes are coexpressed at many diverse sites of cell–cell interaction in the mouse embryo. Dev Biol. 1995;172:126–138. [PubMed]
Bitgood MJ, Shen L, McMahon AP. Sertoli cell signaling by Desert hedgehog regulates the male germline. Curr Biol. 1996;6:298–304. [PubMed]
Bose J, Grotewold L, Ruther U. Pallister-Hall syndrome phenotype in mice mutant for Gli3. Hum Mol Genet. 2002;11:1129–1135. [PubMed]
Brennan J, Tilmann C, Capel B. Pdgfr-alpha mediates testis cord organization and fetal Leydig cell development in the XY gonad. Genes Dev. 2003;17:800–810. [PubMed]
Brokken LJ, Adamsson A, Paranko J, Toppari J. Antiandrogen exposure in utero disrupts expression of desert hedgehog and insulin-like factor 3 in the developing fetal rat testis. Endocrinology. 2009;150:445–451. [PubMed]
Canto P, Soderlund D, Reyes E, Mendez JP. Mutations in the desert hedgehog (DHH) gene in patients with 46,XY complete pure gonadal dysgenesis. J Clin Endocrinol Metab. 2004;89:4480–4483. [PubMed]
Canto P, Vilchis F, Soderlund D, Reyes E, Mendez JP. A heterozygous mutation in the desert hedgehog gene in patients with mixed gonadal dysgenesis. Mol Hum Reprod. 2005;11:833–836. [PubMed]
Carpenter D, Stone DM, Brush J, Ryan A, Armanini M, Frantz G, Rosenthal A, de Sauvage FJ. Characterization of two patched receptors for the vertebrate hedgehog protein family. Proc Natl Acad Sci USA. 1998;95:13630–13634. [PubMed]
Chari NS, McDonnell TJ. The sonic hedgehog signaling network in development and neoplasia. Adv Anat Pathol. 2007;14:344–352. [PubMed]
Chen X, Horiuchi A, Kikuchi N, Osada R, Yoshida J, Shiozawa T, Konishi I. Hedgehog signal pathway is activated in ovarian carcinomas, correlating with cell proliferation: It’s inhibition leads to growth suppression and apoptosis. Cancer Sci. 2007;98:68–76. [PubMed]
Ching S, Vilain E. Targeted disruption of sonic hedgehog in the mouse adrenal leads to adrenocortical hypoplasia. Genesis. 2009;47:628–637. [PubMed]
Clark AM, Garland KK, Russell LD. Desert hedgehog (Dhh) gene is required in the mouse testis for formation of adult-type Leydig cells and normal development of peri-tubular cells and seminiferous tubules. Biol Reprod. 2000;63:1825–1838. [PubMed]
Clarren SK, Alvord EC, Jr, Hall JG. Congenital hypothalamic hamartoblastoma, hypopituitarism, imperforate a.u., and postaxial polydactyly—A new syndrome? Part II: Neuropathological considerations. Am J Med Genet. 1980;7:75–83. [PubMed]
Cui S, Ross A, Stallings N, Parker KL, Capel B, Quaggin SE. Disrupted gonadogenesis and male-to-female sex reversal in Pod1 knockout mice. Development (Cambridge, England) 2004;131:4095–4105. [PubMed]
Dai P, Akimaru H, Tanaka Y, Maekawa T, Nakafuku M, Ishii S. Sonic hedgehog-induced activation of the Gli1 promoter is mediated by GLI3. J Biol Chem. 1999;274:8143–8152. [PubMed]
Ford JK, Young RW. Cell proliferation and displacement in the adrenal cortex of young rats injected with tritiated thymidine. Anat Rec. 1963;146:125–137. [PubMed]
Giuili G, Shen WH, Ingraham HA. The nuclear receptor SF-1 mediates sexually dimorphic expression of Mullerian inhibiting substance, in vivo. Development (Cambridge, England) 1997;124:1799–1807. [PubMed]
Hall JG, Pallister PD, Clarren SK, Beckwith JB, Wiglesworth FW, Fraser FC, Cho S, Benke PJ, Reed SD. Congenital hypothalamic hamartoblastoma, hypopituitarism, imperforate a.u. and postaxial polydactyly—A new syndrome? Part I: Clinical, causal, and pathogenetic considerations. Am J Med Genet. 1980;7:47–74. [PubMed]
Huang CJ, Bingham NC, Parker KL, Yao HH. Sonic hedgehog is essential for proliferation of adrenal subcapsular cells in mouse embryos. The XII Adrenal Cortex Conference; San Francisco. 2008a.
Huang CJ, Bingham NC, Parker KL, Yao HH. Sonic hedgehog is required for adrenal development in mouse embryos. The Endocrine Society’s 90th Annual Meeting; San Francisco. 2008b.
Huang CJ, Barsoum IB, Miyagawa S, Matsumaru D, Parker KL, Yao HH. Progenitor cell expansion and organ size of mouse adrenal is regulated by sonic hedgehog. Endocrinology. 2010;151:1119–1128. [PubMed]
Iannaccone P, Morley S, Skimina T, Mullins J, Landini G. Cord-like mosaic patches in the adrenal cortex are fractal: Implications for growth and development. FASEB J. 2003;17:41–43. [PubMed]
Ikeda Y, Shen WH, Ingraham HA, Parker KL. Developmental expression of mouse steroidogenic factor-1, an essential regulator of the steroid hydroxylases. Mol Endocrinol (Baltimore, MD) 1994;8:654–662. [PubMed]
Ikeda Y, Luo X, Abbud R, Nilson JH, Parker KL. The nuclear receptor steroidogenic factor 1 is essential for the formation of the ventromedial hypothalamic nucleus. Mol Endocrinol (Baltimore, MD) 1995;9:478–486. [PubMed]
Ingham PW, McMahon AP. Hedgehog signaling in animal development: Paradigms and principles. Genes Dev. 2001;15:3059–3087. [PubMed]
Jameson JL. Of mice and men: The tale of steroidogenic factor-1. J Clin Endocrinol Metab. 2004;89:5927–5929. [PubMed]
Jones IC. Variation in the mouse adrenal cortex with special reference to the zona reticularis and to brown degeneration, together with a discussion of the ‘cell migration’ theory. Q J Microsc Sci. 1948;s3–89:53–73. [PubMed]
Kang S, Graham JM, Jr, Olney AH, Biesecker LG. GLI3 frameshift mutations cause autosomal dominant Pallister-Hall syndrome. Nat Genet. 1997;15:266–268. [PubMed]
Kasper M, Jaks V, Fiaschi M, Toftgard R. Hedgehog signalling in breast cancer. Carcinogenesis. 2009;30:903–911. [PMC free article] [PubMed]
Keegan CE, Hammer GD. Recent insights into organogenesis of the adrenal cortex. Trends Endocrinol Metab. 2002;13:200–208. [PubMed]
Kim AC, Hammer GD. Adrenocortical cells with stem/progenitor cell properties: Recent advances. Mol Cell Endocrinol. 2007;265–266:10–16. [PMC free article] [PubMed]
Kim AC, Barlaskar FM, Heaton JH, Else T, Kelly VR, Krill KT, Scheys JO, Simon DP, Trovato A, Yang WH, Hammer GD. In search of adrenocortical stem and progenitor cells. Endocr Rev. 2009;30:241–263. [PubMed]
King P, Paul A, Laufer E. Shh signaling regulates adreno-cortical development and identifies progenitors of steroidogenic lineages. Proc Natl Acad Sci USA. 2009;106:21185–21190. [PubMed]
Luo X, Ikeda Y, Parker KL. A cell-specific nuclear receptor is essential for adrenal and gonadal development and sexual differentiation. Cell. 1994;77:481–490. [PubMed]
McMahon AP, Ingham PW, Tabin CJ. Developmental roles and clinical significance of hedgehog signaling. Curr Top Dev Biol. 2003;53:1–114. [PubMed]
Morohashi KI, Omura T. Ad4BP/SF-1, a transcription factor essential for the transcription of steroidogenic cytochrome P450 genes and for the establishment of the reproductive function. FASEB J. 1996;10:1569–1577. [PubMed]
Nef S, Parada LF. Cryptorchidism in mice mutant for Insl3. Nat Genet. 1999;22:295–299. [PubMed]
Park SY, Meeks JJ, Raverot G, Pfaff LE, Weiss J, Hammer GD, Jameson JL. Nuclear receptors Sf1 and Dax1 function cooperatively to mediate somatic cell differentiation during testis development. Development (Cambridge, England) 2005;132:2415–2423. [PubMed]
Park SY, Tong M, Jameson JL. Distinct roles for steroidogenic factor 1 and desert hedgehog pathways in fetal and adult Leydig cell development. Endocrinology. 2007;148:3704–3710. [PubMed]
Pelusi C, Ikeda Y, Zubair M, Parker KL. Impaired follicle development and infertility in female mice lacking steroidogenic factor 1 in ovarian granulosa cells. Biol Reprod. 2008;79:1074–1083. [PMC free article] [PubMed]
Perrone RD, Bengele HH, Alexander EA. Sodium retention after adrenal enucleation. Am J Physiol. 1986;250:E1–E12. [PubMed]
Pierucci-Alves F, Clark AM, Russell LD. A developmental study of the Desert hedgehog-null mouse testis. Biol Reprod. 2001;65:1392–1402. [PubMed]
Ren Y, Cowan RG, Harman RM, Quirk SM. Dominant activation of the hedgehog signaling pathway in the ovary alters theca development and prevents ovulation. Mol Endocrinol (Baltimore, MD) 2009;23:711–723. [PubMed]
Rice DA, Mouw AR, Bogerd AM, Parker KL. A shared promoter element regulates the expression of three steroidogenic enzymes. Mol Endocrinol (Baltimore, MD) 1991;5:1552–1561. [PubMed]
Rohatgi R, Milenkovic L, Scott MP. Patched1 regulates hedgehog signaling at the primary cilium. Science. 2007;317:372–376. [PubMed]
Russell MC, Cowan RG, Harman RM, Walker AL, Quirk SM. The hedgehog signaling pathway in the mouse ovary. Biol Re-prod. 2007;77:226–236. [PubMed]
Sadovsky Y, Crawford PA, Woodson KG, Polish JA, Clements MA, Tourtellotte LM, Simburger K, Milbrandt J. Mice deficient in the orphan receptor steroidogenic factor 1 lack adrenal glands and gonads but express P450 side-chain-cleavage enzyme in the placenta and have normal embryonic serum levels of corti-costeroids. Proc Natl Acad Sci USA. 1995;92:10939–10943. [PubMed]
Salmon TN, Zwemer RL. A study of the life history of corticoadrenal gland cells of the rat by means of trypan blue injections. Anat Rec. 1941;80:421–429.
Sekido R, Lovell-Badge R. Sex determination and SRY: Down to a wink and a nudge? Trends Genet. 2009;25:19–29. [PubMed]
Shen WH, Moore CC, Ikeda Y, Parker KL, Ingraham HA. Nuclear receptor steroidogenic factor 1 regulates the Mullerian inhibiting substance gene: A link to the sex determination cascade. Cell. 1994;77:651–661. [PubMed]
Sheng T, Chi S, Zhang X, Xie J. Regulation of Gli1 localization by the cAMP/protein kinase A signaling axis through a site near the nuclear localization signal. J Biol Chem. 2006;281:9–12. [PubMed]
Shinoda K, Lei H, Yoshii H, Nomura M, Nagano M, Shiba H, Sasaki H, Osawa Y, Ninomiya Y, Niwa O, Morohashi K, Li E. Developmental defects of the ventromedial hypothalamic nucleus and pituitary gonadotroph in the Ftz-F1 disrupted mice. Dev Dyn. 1995;204:22–29. [PubMed]
Skelton FR. Adrenal regeneration and adrenal-regeneration hypertension. Physiol Rev. 1959;39:162–182. [PubMed]
Spicer LJ, Sudo S, Aad PY, Wang LS, Chun SY, Ben-Shlomo I, Klein C, Hsueh AJ. The hedgehog-patched signaling pathway and function in the mammalian ovary: A novel role for hedgehog proteins in stimulating proliferation and steroidogenesis of theca cells. Reproduction. 2009;138:329–339. [PubMed]
Szczepny A, Hogarth CA, Young J, Loveland KL. Identification of hedgehog signaling outcomes in mouse testis development using a hanging drop-culture system. Biol Reprod. 2009;80:258–263. [PMC free article] [PubMed]
Tempe D, Casas M, Karaz S, Blanchet-Tournier MF, Concordet JP. Multisite protein kinase A and glycogen synthase kinase 3beta phosphorylation leads to Gli3 ubiquitination by SCFbetaTrCP. Mol Cell Biol. 2006;26:4316–4326. [PMC free article] [PubMed]
Tremblay JJ, Robert NM, Lague E. Nuclear receptors, testosterone, and posttranslational modifications in human INSL3 promoter activity in testicular Leydig cells. Ann N Y Acad Sci. 2009;1160:205–212. [PubMed]
Umehara F, Tate G, Itoh K, Yamaguchi N, Douchi T, Mitsuya T, Osame M. A novel mutation of desert hedgehog in a patient with 46,XY partial gonadal dysgenesis accompanied by minifascicular neuropathy. Am J Hum Genet. 2000;67:1302–1305. [PubMed]
Varjosalo M, Taipale J. Hedgehog: Functions and mechanisms. Genes Dev. 2008;22:2454–2472. [PubMed]
Wang B, Li Y. Evidence for the direct involvement of {beta}TrCP in Gli3 protein processing. Proc Natl Acad Sci USA. 2006;103:33–38. [PubMed]
Wijgerde M, Ooms M, Hoogerbrugge JW, Grootegoed JA. Hedgehog signaling in mouse ovary: Indian hedgehog and desert hedgehog from granulosa cells induce target gene expression in developing theca cells. Endocrinology. 2005;146:3558–3566. [PubMed]
Yao HH, Capel B. Disruption of testis cords by cyclopamine or forskolin reveals independent cellular pathways in testis organo-genesis. Dev Biol. 2002;246:356–365. [PubMed]
Yao HH, Whoriskey W, Capel B. Desert Hedgehog/Patched 1 signaling specifies fetal Leydig cell fate in testis organogenesis. Genes Dev. 2002;16:1433–1440. [PubMed]
Zajicek G, Ariel I, Arber N. The streaming adrenal cortex: Direct evidence of centripetal migration of adrenocytes by estimation of cell turnover rate. J Endocrinol. 1986;111:477–482. [PubMed]
Zimmermann S, Schwarzler A, Buth S, Engel W, Adham IM. Transcription of the Leydig insulin-like gene is mediated by steroidogenic factor-1. Mol Endocrinol (Baltimore, MD) 1998;12:706–713. [PubMed]
Zubair M, Parker KL, Morohashi K. Developmental links between the fetal and adult zones of the adrenal cortex revealed by lineage tracing. Mol Cell Biol. 2008;28:7030–7040. [PMC free article] [PubMed]
Zwemer RL, Wotton RM, Norkus MG. A study of corticoadrenal cells. Anat Rec. 1938;72:249–263.