AbstractIn general adrenal glands and gonads play a veryimportant role in sex differentiation and steroidogenesis. These two aresystems are closely related as they share a common region of origin i.e.mesoderm and both are involved in steroidogenesis.
Various biological eventsoccur during adrenal and gonadal steroidogenesis. In this article transcription factors and important signaling pathwaysinvolved in regulation of steroidogenesis and adrenal growth have beensummarized. Present review illustrates various novel signaling pathways suchSonic hedgehog ,Wnt, Notch, ?-catenin involved in adrenal gland morphology andits functions that are deeply interconnected.
Certain nuclear receptor such asSteroidogenic Factor-1 which acts as critical regulator for the development andhomeostasis of the adrenal cortex and gonads. SF-1 is a nuclear receptorthat is expressed exclusively in the steroidogenic tissues of the hypothalamicpituitary-adrenal/gonadal axis. Protein kinase such as Mitogen-activated protein kinases which areserine/threonine kinases are majorly involved in the expression of the crucialprotein Steroidogenic acute regulatory protein in steroidogenesis. Characterization of certain proteins that are encoded by dax1, amh, and cyp19a1 whichplays very important role in gonad differentiation and to evaluate the relationbetween gonadal expression of StAR ,Fushitarazu factor-1, and cytochrome P450-11A in reproduction. This article aimed to describe the varioussignaling mechanisms and novel transcription factors involved at genomic levelin common to adrenal and gonadal development in fishes and lower vertebrates. Keywords: Gonadal development; Sex differentiation; SteroidogenicFactor-1; Adrenal growth;; Steroidogenic acuteregulatory protein; Mitogen-activated protein kinases; Introduction Steroidogenesis involves the synthesis of steroidhormones that are derivatives of cholesterol which are synthesized by varioustissues, most prominently the adrenal gland and gonads.
These are usually found inchordates and arthropods. Fishes, for exampleteleosts, produce several types of bioactive gonadal steroids, includingprogestogens, estrogens, androgens and various derivatives of steroids.Steroids are required for development, homeostasis ,maintenance, andreproduction. In adult vertebrates, these steroids are produced at appropriatetimes in steroid producing cells termed as gonads. These cells express various group of steroidogenic enzyme genes thatusually modify cholesterol and its derivatives 1.
These steroids playa different role even though they are chemically identical in major of the vertebrates. Steroidhormones usually produced by steroidogenic cells, that include ovary, testisand brain thatare required for reproduction and bodily homeostasis. 2.
Theacute and chronic regulation of steroidogenesis is controlled by trophichormones that normally occur in order of minutes and hours, respectively.Chronic regulation of steroidogenesis by LH or ACTH occurs at the level of genetranscription 3. Cholesterolis metabolized to pregnenolone through cytochrome P450 cholesterol side chain cleavage enzyme and transferred fromouter to inner mitochondrial membrane. This is regulated by the Steroidogenic acute regulatory (StAR) proteinthe one which regulates the truerate-limiting step in steroid biosynthesis 4. This central role of StAR proteinregulation was proven by two observations 5, 6. Sex differentiation is initiated and controlled by gonadal steroidhormones.
These hormones perform differentfunctions during development into sexorgans. This is regulated by the expression of proteins produced by certains signalling pathway suchas cAMP-dependent mechanism inthe adrenal and gonads. Gonadal developmentReproductionin vertebrates depends on function of twogametes that is sperm and eggs that develop into different organs i.e , the testisand the ovary. These two organs are grossly different and composed of common cell lineages, interstitialcells, supporting cells and germ cells. Each mature ovary composed of anovarian cavity, stromal compartment and germinal epithelium. In fishes such asteleosts, the germ line stem cells resides in germinal epithelium and mitoticallyproduce active oogonia . This structure is similar to that of surfaceepithelium present in mammals.
The steroid hormones are produced by follicles whichhelps the oocytes to grow that reside in stromal compartment. In case oftestis,the spermatogenesis starts from the germ line stem cells till the spermproduction that usually occurs in tubules , and the interstitial tissue producingthese hormones resides between these structures. Factors involved during gonadal developmentGerm cells that not have been reached to the gonad attheir early stages are termed as primordial germ cells (PGC).
These primordialgerm cells were identified morphologically and specified functionally by the distribution ofcytoplasmic determinants that includes RNA-binding proteins such as VASA, NANOSand TUDOR and that were restricted asgranular-like structures or nuage 7. This similarity have been previously found in somelower vertebrates and Drosophila. Nanos3 was found to be the earliest marker insome fish such as medaka, and by using this, PGCs were identified first during earlygastrulation stage 8. Three mechanically distinct modes were observed for migration of PGCs 8, 9. In the early gastrulation stage the chemokinereceptor CXCR4 and its ligand, SDF1A were involved in migration towards the marginal zone. Duringthe late gastrulation and early somitogenesis stages, it is dependent on theconvergent movement of the somatic cells. Later during the bilateral alignmentthe primordial stem cells governs the interactions between CXCR4 and SDF1B, whichresume its activity and migrates towards the posterior end of lateral plate mesoderm,where the somatic precursors of gonads arise10. In teleosts, granulosacells and sertoli cells shared a common origin, specifically supporting cells thatexpress sox9b gene in bipotential gonadal primordia.
Both supporting cells showedthe expression of sox9b 11, an observation in contrast to the situationof mammals, where only sox9 was expressed in Sertoli cells that are requiredfor testicular development 12, 13. Sox9 along with (SF-1) steroidogenic factor 1, regulates the transcription of anti-Mullerian hormone (AMH) gene. The SOX-9 gene plays a very important role in male sexual development.These cells that express sox9b start toexpress dmrt1, indicating the differentiationto Sertoli cells. In the early stage of oogenesis, from germ line stem cells toan early diplotene oocytes it proceeds to form cradle structures.
Subsequently thesediplotene oocytes that surrounds the somatic cells exit from the germinalcradle and will recruit theca cells to form the follicles. Theca cell layer formation is an importantphysiological event that occurs during early follicular development. Finally theese follicles that are presnt instromal compartment possess two layers of somatic cells termed as innergranulosa cells and outer theca cells. Granulosa and theca cells of the ovary act as asupport to germ cells within thedeveloping follicle. During this process, the granulosa cells will lose theexpression of sox9b while foxl2, that isa marker of granulosa cells, gets activated 11, 14. This suggests that granulosa cells which areoriginated from the sox9b -expressing cells, both follicular formation andoocyte will exit from germinal cradles and depends upon a series of successiveprocesses 14 which is also observed in other teleost fishby histological analysis 15, 16. In somestudies it indicated that sox9b and amh,that are involved in testicular differentiation in vertebrates, were implicatedin testicular formation and spermatogenesis during the sex change as well.Sox9 expression was intensively observed in the sertoli cells of testis thatare located more distantly in lobules.
In ovary, sox9b was expressed in thegerminal cradles representing niche regions. The most important function ofsox9b-expressing cells is to maintain the stem type germ cells during earlystages of gametogenesis. In some studies, they have observed the functions of dmrt1 and amh during male germ cell development by creating the mutants withthe use of Crispr/cas9 technology in zebrafish. Both female and male amh mutants developed hypertrophicgonads because of uncontrolled proliferation as well as impaired differentiationof germ cells whereas amh mutantzebrafish showed female-based sex ratio. It was also found that amh helpsin controlling the balance between proliferation as well as differentiation of male germ cells.
But dmrt1 isusually required for self-renewal, maintenance as well as during differentiationof male germ cells. During the process of testicular development, the genes which are requiredfor the production of steroid hormones such as p450scc/cyp11a1 and hsd3b, starts to express in Leydig cells that are located in themarginal regions of lobules. These genes have been expressed in ftz-f1 -expressing cells during the testiculardevelopment 17.It suggests that ftzf1 regulates various sets of steroidogenic genes and thatare involved in the androgen production thatmay normally occur in a single cell lineage of ftz-f1 expressing cells. In certainfishes such as rainbow trout, immunohistochemical analysis revealed that HSD3B,P450c17/CYP17A1, P45011B/CYP11B, , P450scc/ CYP11A1 and P450c17/CYP17A1 wereall co-localized in the interstitialLeydig cells 18.Atleast two types of theca cells were seem to bepresent in certain fish such as medaka during the ovarian development.
Somefishes express only aromatase. P450c17 and aromatase were expressed exclusivelyin transgenic medaka fish by expression analysis using aromatase-reporter 19.Alternatively, the two types of theca cells have been to share a commonprecursor that normally expressed theftz-f1 gene, by which generating an offspring capable of either by maintainingor down regulating ftz-f1 expression and initiating the aromatase expression 20.
AdrenaldevelopmentIn vertebrates, adrenal glands consists of twodistinct parts, outer adrenal cortex and inner adrenal medulla. The outer adrenalcortex secretes three major hormones referred as glucocorticoids, mineralocorticoidsand adrenal androgens. Adrenal androgens involved in the gender differentiationin human beings mainly dehydroepiandrosterone (DHEA) and testosterone. Cellularorganization of gonads is similar in all vertebrates, based on differentprogression can trigger bipotential gonads, forms either ovaries or testis.Gonads are originated from the embryonicmesonephros with the thickening of ventrolateral surface which is termed as genitalridge.
In the classic experiment of Jost 21 female differentiation has been observedirrespective of the genetic sex in the absence of testicular hormones. Incertain expression analysis , it was observed that GATA4 was involved in sexdetermination 22,23.The role of GATA4 in the regulation of gene expression was also observed by in vitro analysis data in the gonadsdownstream of Sry, including inhibin ? , Mis, andsteroidogenic acute regulatory protein(StAR) 24,25.In vertebrates, the steroid hormones of the adrenalgland show a different adaptiveresponses during the internal and external environmental stress conditions.
Sexdetermination region of Y chromosome (SRY) gene required to initiate thesignaling for male gonadal differentiation. Many other genes involved in gonadogenesisare GATA4 and FOG2 26.In mammals, gonads arise from bilateral genital ridge in both sexes that usuallydevelop as ovaries or testes 27,28.In humans gonadal differentiation occurs from the 10th through 12thembryonic week.