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Abstract

In general adrenal glands and gonads play a very
important role in sex differentiation and steroidogenesis. These two are
systems are closely related as they share a common region of origin i.e.
mesoderm and both are involved in steroidogenesis. Various biological events
occur during adrenal and gonadal steroidogenesis. In this article transcription factors and important signaling pathways
involved in regulation of steroidogenesis and adrenal growth have been
summarized. Present review illustrates various novel signaling pathways such
Sonic hedgehog ,Wnt, Notch, ?-catenin involved in adrenal gland morphology and
its functions that are deeply interconnected. Certain nuclear receptor such as
Steroidogenic Factor-1 which acts as critical regulator for the development and
homeostasis of the adrenal cortex and gonads. SF-1 is a nuclear receptor
that is expressed exclusively in the steroidogenic tissues of the hypothalamic
pituitary-adrenal/gonadal axis. Protein kinase such as  Mitogen-activated protein kinases which are
serine/threonine kinases are majorly involved in the expression of the crucial
protein Steroidogenic acute regulatory protein in steroidogenesis. Characterization  of certain proteins that are encoded by dax1, amh, and cyp19a1 which
plays very important role in gonad differentiation and to evaluate the relation
between gonadal expression of StAR ,Fushi
tarazu factor-1, and cytochrome P450-11A in reproduction. This article aimed to describe the various
signaling mechanisms and novel transcription factors involved at genomic level
in common to adrenal and gonadal development in fishes and lower vertebrates.

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Keywords: Gonadal development; Sex differentiation; Steroidogenic
Factor-1; Adrenal growth;; Steroidogenic acute
regulatory protein; Mitogen-activated protein kinases;

 

 

 

 

 

Introduction

 

Steroidogenesis involves the synthesis of steroid
hormones that are derivatives of cholesterol which are synthesized by various
tissues, most prominently the adrenal gland and gonads. These are usually found in
chordates and arthropods. Fishes, for example
teleosts, produce several types of bioactive gonadal steroids, including
progestogens, estrogens, androgens and various derivatives of steroids.
Steroids are required for development, homeostasis ,maintenance, and
reproduction. In adult vertebrates, these steroids are produced at appropriate
times in steroid producing cells termed as gonads. These cells express various  group of steroidogenic enzyme genes that
usually modify cholesterol and its derivatives 1. These steroids play
a different role even though they are chemically identical in major of the vertebrates.

 

 

Steroid
hormones usually produced by steroidogenic cells, that include ovary, testis
and brain that
are required for reproduction  and bodily homeostasis. 2. The
acute and chronic regulation of steroidogenesis is controlled by trophic
hormones that normally occur in  order of minutes and hours, respectively.
Chronic regulation of steroidogenesis by LH or ACTH occurs at the level of gene
transcription 3. Cholesterol
is metabolized to pregnenolone through cytochrome P450 cholesterol side chain cleavage enzyme and transferred from
outer to inner mitochondrial membrane. This is regulated by the  Steroidogenic acute regulatory (StAR) protein
the one which regulates the true
rate-limiting step in steroid biosynthesis 4. This central role of StAR protein
regulation was proven by two observations 
5, 6. Sex differentiation is initiated and controlled by gonadal steroid
hormones. These hormones perform different
functions during development  into sex
organs. This is regulated by the expression of proteins  produced by certains signalling pathway such
as  cAMP-dependent mechanism in
the adrenal and gonads.

 

 

 

Gonadal development

Reproduction
in vertebrates depends on function  of two
gametes that is sperm and eggs that develop into different organs i.e , the testis
and the ovary. These two organs are grossly different  and composed of common cell lineages, interstitial
cells, supporting cells and germ cells. Each mature ovary composed of an
ovarian cavity, stromal compartment and germinal epithelium. In fishes such as
teleosts, the germ line stem cells resides in germinal epithelium and mitotically
produce active oogonia . This structure is similar to that of surface
epithelium present in mammals. The steroid hormones are produced by follicles which
helps the oocytes to grow that reside in stromal compartment. In case of
testis,the spermatogenesis starts from the germ line stem cells till the sperm
production that usually occurs in tubules , and the interstitial tissue producing
these hormones resides between these structures.

 

Factors involved during gonadal development

Germ cells that not have been reached to the gonad at
their early stages are termed as primordial germ cells (PGC). These primordial
germ cells were identified morphologically and specified  functionally by the distribution of
cytoplasmic determinants that includes RNA-binding proteins such as VASA, NANOS
and TUDOR and that were restricted  as
granular-like structures or nuage 7. This similarity have been previously found in some
lower vertebrates and Drosophila. Nanos3 was found to be the earliest marker in
some fish such as medaka, and by using this, PGCs were identified first during early
gastrulation stage 8. Three mechanically 
distinct modes were observed for migration of PGCs 8, 9. In the early gastrulation stage the chemokine
receptor CXCR4 and its ligand, SDF1A were involved in  migration towards the marginal zone. During
the late gastrulation and early somitogenesis stages, it is dependent on the
convergent movement of the somatic cells. Later during the bilateral alignment
the primordial stem cells governs the interactions between CXCR4 and SDF1B, which
resume its activity and migrates towards the posterior end of lateral plate mesoderm,
where the somatic precursors of gonads arise10.

 

In teleosts, granulosa
cells and sertoli cells shared a common origin, specifically supporting cells that
express sox9b gene in bipotential gonadal primordia. Both supporting cells showed
the expression  of sox9b 11, an observation in contrast to the situation
of mammals, where only sox9 was expressed in Sertoli cells that are required
for 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  to
express dmrt1, indicating  the differentiation
to Sertoli cells. In the early stage of oogenesis, from germ line stem cells to
an early diplotene oocytes it proceeds to form cradle structures. Subsequently these
diplotene oocytes that surrounds the somatic cells exit from the germinal
cradle and will recruit theca cells to form the follicles. Theca cell layer formation is an important
physiological event that occurs during early follicular development.

 Finally theese follicles that are presnt in
stromal compartment possess two layers of somatic cells termed as inner
granulosa cells  and outer theca cells. Granulosa and theca cells of the ovary act as a
support  to germ cells within the
developing follicle.  During this process,
 the granulosa cells will lose the
expression of  sox9b while foxl2, that is
a marker of granulosa cells, gets activated 11, 14. This suggests that granulosa cells which are
originated from the sox9b -expressing cells, both follicular formation and
oocyte will exit from germinal cradles and depends upon a series of successive
processes 14 which is also observed in other teleost fish
by histological analysis 15, 16. In some
studies it indicated that sox9b and amh,
that are involved in testicular differentiation in vertebrates, were implicated
in testicular formation and spermatogenesis during the sex change as well.
Sox9 expression was intensively observed in the sertoli cells of testis that
are located more distantly in lobules. In ovary, sox9b was expressed in the
germinal cradles representing niche regions. The most important function of
sox9b-expressing cells is to maintain the stem type germ cells during early
stages of gametogenesis. In some studies, they have observed the functions of dmrt1 and amh during male germ cell development by creating the mutants with
the use of Crispr/cas9 technology in zebrafish. Both female and male amh mutants developed hypertrophic
gonads because of uncontrolled proliferation as well as impaired differentiation
of germ cells whereas amh mutant
zebrafish showed female-based sex ratio.

 It was also found that amh  helps
in controlling the balance between proliferation as well as  differentiation of male germ cells. But dmrt1 is
usually required for self-renewal,  maintenance as well as during differentiation
of male germ cells. During the process of  testicular development, the genes which are required
for the production of steroid hormones such as  p450scc/cyp11a1 and hsd3b, starts to express in Leydig cells that are located in the
marginal regions of lobules. These genes have been expressed in  ftz-f1 -expressing cells during the testicular
development 17.
It suggests that ftzf1 regulates various sets of steroidogenic genes and that
are involved in the  androgen production that
may normally occur in a single cell lineage of ftz-f1 expressing cells. In certain
fishes such as rainbow trout, immunohistochemical analysis revealed that HSD3B,
P450c17/CYP17A1, P45011B/CYP11B, , P450scc/ CYP11A1 and P450c17/CYP17A1 were
all co-localized in the  interstitial
Leydig cells 18.

Atleast two types of theca cells were seem to be
present in certain fish such as medaka during the ovarian development. Some
fishes express only aromatase. P450c17 and aromatase were expressed exclusively
in transgenic medaka fish by expression analysis using aromatase-reporter 19.
Alternatively, the two types of theca cells have been to share a common
precursor that normally expressed  the
ftz-f1 gene, by which generating an offspring capable of either by maintaining
or down regulating ftz-f1 expression and initiating the aromatase expression 20.

Adrenal
development

In vertebrates, adrenal glands consists of two
distinct parts, outer adrenal cortex and inner adrenal medulla. The outer adrenal
cortex secretes three major hormones referred as glucocorticoids, mineralocorticoids
and adrenal androgens. Adrenal androgens involved in the gender differentiation
in human beings mainly dehydroepiandrosterone (DHEA) and testosterone. Cellular
organization of gonads is similar in all vertebrates, based on different
progression can trigger bipotential gonads, forms either ovaries or testis.
Gonads are originated  from the embryonic
mesonephros with the thickening of ventrolateral surface which is termed as genital
ridge. In the classic experiment of Jost 21
 female differentiation has been observed
irrespective of the genetic sex in the absence of testicular hormones. In
certain expression analysis , it was observed that GATA4 was involved in sex
determination 22,
23.
The role of GATA4 in the regulation of gene expression was also observed by in vitro analysis data in the gonads
downstream of  Sry, including inhibin ? , Mis, and
steroidogenic acute regulatory protein(StAR) 24,
25.

In vertebrates, the steroid hormones of the adrenal
gland  show a different adaptive
responses during the internal and external environmental stress conditions. Sex
determination region of Y chromosome (SRY) gene required to initiate the
signaling for male gonadal differentiation. Many other genes involved in gonadogenesis
are GATA4 and FOG2 26.
In mammals, gonads arise from bilateral genital ridge in both sexes that usually
develop as ovaries or testes 27,
28.
In humans gonadal differentiation occurs from the 10th through 12th
embryonic week. Steroidogenic factor 1 (SF-1) transcription factor
critical for adrenocortical development and homeostasis. SF1 is also known as
adrenal four-binding protein or nuclear hormone receptor Ad4BP, encoded by the
gene NR5A1. All cells that belong to steroidogenic lineages of the adrenal and
gonads express SF1, including subpopulations of long-term retained progenitor
cells in each organ 29, 30. Therefore, SF1 expression defines the identity of
these cells and commitment to steroidogenic differentiation 31-33. The expression of SF1 is detectable early in fetal
life, between the AGP formation and the ultimate establishment of the adrenal
primordium 30. Genetic loss of Nr5a1 or its upstream
transcriptional regulators Pbx1, Wt1, and Cited2, interferes with AGP formation
leading to various degrees of adrenal hypoplasia in mice 34-36. While Nr5a1 is continuously expressed from the
time of adrenal primordium formation throughout the adult life, during
embryonic stages and early fetal life in mice, the Nr5a1 expression is driven
by the fetal adrenal-specific enhancer (FAdE), which becomes inactive when the
definitive cortex forms, suggesting that distinct mechanisms sustain Nr5a1
expression in the fetal and in the definitive cortex . 

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