Steroidogenesis required for normal reproductive function and bodily homeostasis.

 Steroidogenesis involves the synthesis of steroid hormones that arederivatives of cholesterol which are synthesized by various tissues, mostprominently 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, maintenance, homeostasis andreproduction.

Steroids direct the development of germ cells andaccessory glands and organs, as well as the modification of the behaviour, toensure that sexual reproduction can take place. In adult vertebrates, these steroids are produced atappropriate times in specialized steroid producing cells called gonads. Thesecells express a group of steroidogenic enzyme genes whose products modify itscholesterol and derivatives1.Although manysteroids are identical chemically in all major vertebrate classes, the role ofthese steroids may differ.

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However steroid hormones have evolved in somevertebrate classes, especially amongst fishes, to fulfil particular functions. Steroid hormones are producedbysteroidogenic cells of the ovary testis and brain that are required for normal reproductive function and bodily homeostasis.Steroidogenic endocrine tissues such as the adrenal and the gonads respond totrophic hormones and other external stimuli with rapid surge in steroid hormoneproduction 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 pregnenoloneby  cytochromeP450 cholesterol side chain cleavageenzyme (p450scc) and transferredfrom the outer to the innermitochondrial membrane. The Steroidogenic acute regulatory (StAR) protein isthe one which regulates the truerate-limiting step in steroid biosynthesis, i.e.

the delivery of cholesterolfrom the outer to the inner mitochondrial membrane 4. The central role of StAR was proven by twoobservations by robust steroid hormone synthesis followed co-transfection ofStAR and the cholesterol side-chain cleavage system into nonsteroidogenic COS-1cells 4, 5. In other patients with StAR mutations havecongenital lipoid adrenal hyperplasia, whereby all adrenal and gonadalsteroidogenesis was distrupted5, 6. Sex differentiation is initiated and controlled by gonadal steroidhormones. These hormones performdifferent functions and permanently differentiated into sex organs duringdevelopment. The expression of this protein is predominantly regulatedby cAMP-dependent mechanism in the adrenal and gonads.Gonadal developmentReproduction in vertebrates depends on function  two distinct gametes, sperm and eggs thatdevelop into different organs, the testis and the ovary.

The two reproductive organs are grossly different, but they both arecomposed of developmentally common cell lineages, supporting cells,interstitial cells and germ cells. Amature ovary consists an ovarian cavity, germinal epithelium and stromalcompartment. In fishes such as teleosts, the germ line stem cells aremitotically active oogonia that reside in germinal epithelium. Their structure wassimilar to surface epithelium in mammals. Steroid hormones are produced by thefollicles that are present in the stromal compartment where the oocytes grow. In the testis, spermatogenesis starting from the germ line stem cells tosperm production occurs in tubules or lobules, and the interstitial tissue thatproduce steroid hormones resides between these structures.The germ cells at their early stages that have not reached the gonad aretermed as primordial germ cells(PGC).

These PGCs were identifiedmorphologically and functionally specified by the distribution of cytoplasmicdeterminants that includes RNA-binding proteins NANOS, TUDOR and VASA whichwere localized on granule-like structures or nuage7. This similarityhave beenpreviously observed in other lower vertebrates and Drosophila. Nanos3was found to be the earliest marker in some fish such as medaka, and using thismarker, PGCs were first identified at an early gastrulation stage 8.Threemechanically  distinct modes wereobserved for migration of PGCs 8, 9.

In theearly gastrulation stage migration towards marginal zone depends on the chemokinereceptor CXCR4 and its ligand, SDF1A. Second, at the late gastrulation andearly somitogenesis stages, it depends on the convergent movement of somaticcells. After aligning bilaterally, PGCs, governed by interactions between CXCR4and SDF1B, resume active and directional migration towards the posterior end ofthe lateral plate mesoderm, where gonadal somatic precursors arise10.In teleosts, Sertoli and granulosacells  share a common origin, namely, the supportingcells expressing the sox9b gene in the bipotential gonadal primordia. Normally sox9b wasfound to be express in both supporting cells 11, an observation that is contrast to thesituation in mammals, where sox9 is only expressed in Sertoli cells and is bothrequired testicular development 12, 13.

Sox9 along with  steroidogenic factor 1, regulates transcription of the anti-Mullerian hormone (AMH) gene.SOX-9 also plays an important role in male sexualdevelopment.The sox9bexpressing cells begin to express dmrt1, indicating the differentiation into Sertolicells. In the early oogenesis, from germ line stem cells to early diploteneoocytes it proceeds in the cradles. Subsequently the diplotene oocytessurrounding somatic cells exit from the germinal cradle and recruit theca cellsto form follicles.Theca cell layer formation isan important physiological event that occur during early follicular development.

Finally the follicles in the stromal compartment have two layers of somaticcells, outer theca cells and inner granulosa cells. Granulosa and theca cells of the ovary act as a support  to germ cells within the developing follicle.During this step, the granulosa cells lose sox9b expression while foxl2,a marker of granulosa cells, is activated 11, 14. This suggests that granulosa cellsoriginate from the sox9b -expressing cells.

Both follicular formation andoocyte exit from germinal cradles appears to depend upon a series of successiveprocesses 14 which is also observed in other teleost fishby histological analysis15, 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.Interestingly,in the testis, sox9b expression is very intense in the Sertoli cells locatedmost distally in the lobules.

In the ovary, sox9b is expressed in the germinalcradles representing niche regions.The common function of sox9b -expressingcells is for the maintenance of stem-type germ cells during earlygametogenesis. In some studies,they examined theroles of amh and dmrt1 in male germcell development by generating theirmutants with Crispr/Cas9 technology in zebrafish. Amh mutantzebrafish displayed a female-biased sex ratio, and both male and female amh mutantsdeveloped hypertrophic gonads due to uncontrolled proliferation and impaireddifferentiation of germ cells.It was also found that amh  acts as aguardian to control the balance between proliferation and differentiation ofmale germ cells, whereas dmrt1 required for the maintenance,self-renewal, and differentiation of male germ cells.Duringtesticular development, genes required for the production of steroidhormone(s), e.

g. p450scc/cyp11a1 and hsd3b,begin to be express in presumptive Leydig cells located in the marginal regionsof the lobule.These genes are expressed in  ftz-f1 -expressing cells during testiculardevelopment 17. This suggests that ftzf1regulates a set of steroidogenic genes and that androgen production may occurin a single cell lineage of ftz-f1 – expressing cells. In rainbow trout,immunohistochemicalanalysis also revealed that P45011B/CYP11B, HSD3B,P450scc/CYP11A1 and P450c17/CYP17A1 were all co-localized in interstitial Leydig cells 18.In  contrast, during ovarian development, at leasttwo types of theca cells seem to be present in medaka.

Some fishes express onlyaromatase. It has also revealedthat p450c17 and aromatase were exclusivelyexpressed in transgenic medaka fish by expression analysis usingaromatase-reporter19. Alternatively, the two types oftheca cells may share a common precursor that expresses the ftz-f1 gene, andthat generates offspring capable of either maintaining or down regulatingftz-f1 expression and initiating aromatase expression20.