Implicating transforming growth factor-β and sex steroids in the regulation of brain-gonadal functions
How to cite this article: Mamta SK. Implicating transforming growth factor-β and sex steroids in the regulation of brain-gonadal functions. J Reprod Healthc Med 2022;3:9.
Transforming growth factor-beta (Tgf-β) significantly mediates TGF signals in the brain and gonadal development. The present study insights into the implication of novel factor Tgf-β and sex steroids in coordination with catecholaminergic activity; moreover, the influence on catecholamines, gonadotropin-releasing hormone (GnRH1), and related transcripts/genes by implanting osmotic pump-mediated mismatches sex steroids in the teleost. The outcome collectively showed the severe effect of estrogenic compounds at the nominal dose over androgenic to alter reproductive conditions. In addition, the differential pattern of key transcription factors/genes revealed significantly higher expression in the brain and gonads than in other organs, which seem to have a role in the hypothalamic-pituitary-gonadal (H-P-G) axis to regulate brain-gonadal functions in catfish. Furthermore, the abundance of crucial factors mRNA and protein expression in the brain suggests a significant role in this correlation. Collectively, the study provides an understanding of the growth factors and sex steroids through dopaminergic system, where upregulated expression levels of GnRH1 vis-a-vis certain brain-related genes, that is, GnRH1, Tgf-β, Gfrα-1, cyp19a1b, tph, and th in teleost revealed their regulatory influence more importantly on the H-P-G axis.
Transforming growth factor-beta
Growth factors typically act as signaling molecules, transforming growth factor-beta (Tgf-β), glial cell line-derived neurotrophic factor (GDNF), and sex steroids are vital regulators for growth, neuronal differentiation, and gonadal functions in response to reproduction, also many other biological processes.[1,2] TGF-β is essential for the development of the persistence and mediator of midbrain dopaminergic (DA-ergic) neurons and also upsurges the tyrosine hydroxylase (Th) expression levels in the brain. Defective signaling pathway regulation transduces the Tgf-β signals, leading to several disorders, such as cancer, cardiovascular, metabolic, neurodegeneration, and other neurological disorders in the central nervous system (CNS). A previous study reported the neuroprotective effects of Tgf-β, receptors (1-3), activin A, and GDNF for DA-ergic neurons in vitro, protein expression increases the survival of Th-immunoreactive DA-ergic in mice and catfish.[5,6] Tgf-β is an essential growth factor involved in various functions, that is, apoptosis, sex differentiation, cellular proliferation, and growth also act as a paracrine factor which plays key roles in gonadal functions such as stimulation of follicular development and steroid hormone 17β-estradiol (E2) and androgen (T) production in mammals. In rainbow trout, Tgf-β stimulates the proliferation of spermatogonial and primordial germ cells and prevents the maturation of oocytes in zebrafish.[10,11] Some members of the Tgf-β exhibit vital functions in reproduction by regulating gonads.[8,12] However, it also upsurges the potency of particular Tgf-β, neurotrophin, fibroblast growth factor-2, brain cell-derived neurotrophic factor (BDNF), ciliary neurotrophic factor, and GDNF which regulate cellular processes during embryogenesis and support DA-ergic system in teleost.[3,13,14] Eliminating the Tgf-β type 2 receptor in DA neurons interrupt Tgf-β1 expression and GABAergic neurons, elevating mammals’ inhibitory input. Prominently, several neurotrophic factors, neurotransmitters/ neuropeptides, and sex steroids are known to regulate gonadotropin (GTH), modulating the gonadotropin-releasing hormone (GnRH), and/or catecholaminergic (CA-ergic) systems at the level of the brain, to succeed reproduction. In CNS sex steroids, E2 and methyltestosterone (MT) are strong regulators of various diseases that occur in organ systems and also regulate the gonadal development and maintain a reproductive system in both sexes.[17,18] Sex steroid E2 controls DA-ergic activity in many ways, that is, neurotransmission in combination with enzymes and anti-DA-ergic producing effects that involve neuron degradation. In addition, DA is the significant inhibitory neurohormone that regulates GTH, whereas the stimulatory influence of norepinephrine (NE) and serotonin (5-HT) on GnRH release.[20,21] Moreover, natural sex steroids are altered by exogenous steroids that can mimic and disturb the neuroendocrine system. McEwen reported that gonadal steroids regulate diverse physiological functions in developing and mature neural targets by the hypothalamic-pituitary-gonadal (H-P-G) axis which further provides access to brain function organizational dealing with neuronal circuits and response capabilities, together with sex differences. The present review highlights the interactions of key growth factors and sex steroids and their regulation in the H-P-G axis and associated vital transcripts/genes, influencing regulatory pathways, and expression profiling to understand the regulation of brain over gonadal functions.
INVOLVEMENT OF GROWTH FACTORS AND OTHER KEY FACTORS IN THE BRAIN AND GONADAL FUNCTIONS
Tgf-β is a crucial growth factor for developing midbrain DAergic neurons in vitro and in vivo. However, in deficient mice, Tgf-β isoform and its receptor have not yet shown a role in CNS development.[24,25] Previously, human immunohistochemical analyses have been observed using specific polyclonal antibodies of Tgf-β1 and Tgf-β2 to identify cellular localization in ovarian tissues of various reproductive stages. Further, ovarian tissue produces Tgf-β1 and Tgf-β2, though Tgf-β1 exists in main ovarian cell types; however, Tgf-β2 is produced by only follicular theca cells and luteal cells. The Tgf-β1 signaling extensively regulates biological responses and various regulatory mechanisms at the molecular level of Tgf-β signaling in the modulation of specific physiological processes also brain and gonadal functions.[3,27] In goldfish, Tgf-β expression of the ovary showed a reduction in androgen production and its vital role in gonadal development at two different stages. The significance of Tgf-β in reproductive function suggests the implication of cytokines in infertility and other sexual dysfunction. Based on this premise, it is worthwhile to investigate the impact of Tgf-β and the modulatory action of a brain-pituitary-gonadal axis. The earlier report investigated Tgf-β as a vital molecule that regulates the survival of neurons synergistically with neurotrophic factors GDNF, BDNF, neurotrophin, and neuropeptides[6,30] in turn, these factors regulate the release of active TGF also modulation of Leydig cell steroidogenesis with androgenic steroids. Our recent finding revealed that the prominent Tgf-β mRNA and protein expression appear to propose a significant impact on growth factor signaling at the level of the brain. Further, TGF-β protein expression in the preoptic area of hypothalamus (POAHYP) by immunolocalization indicates its role in neuronal development through GnRH and GTH axis which might support gonadal functions.
GDNF/GDNF family receptor α-1 (GFRα-1)
Neurotrophic factors typically act as signaling molecules that influence the development and differentiation of many central and peripheral neuronal cells in response to reproduction. GDNF predominantly binds to GFRα-1 by modulating several central neurons including DA-ergic neurons in the brain and protects against neurodegeneration. The complex GDNF-GFRα-1 recruits the tyrosine kinase transmembrane protein to upshot DA-ergic neurons differentiation.[32-34] In the neuroendocrine system brain, glial cells are an abundant cell type[35,36] that produces neurosteroids such as estradiol-E2, T, and neurotrophic factor GDNF in teleost.[6,38] Earlier studies confirmed that GDNF upsurges the DA uptake and Th expression and promotes the growth of midbrain DAergic neurons. Furthermore, GDNF acts as a neurotrophic factor in motor neurons and noradrenergic neurons in the CNS.[39,40] Our previous findings reported immunolocalization of GFRα-1 which exposed its presence in preoptic POAHYP in adult catfish. Furthermore, siRNA transient silencing showed a lower expression level of Gfrα-1 and down-regulated the brain-related gene expression. In catfish brains, Gfrα-1 expression declined on the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, MPTP treatment triggering neurodegeneration, when further correlated with catecholamines (CAs), L-3,4-dihydroxyphenylalanine, DA, and NE levels, which conceivably entrains GnRH and GtH axis, by targeting CA-ergic activity moderately. In addition, GDNF has neurotrophic and anti-apoptotic properties, which delay homeostasis of DA at different levels, that is, stimulation of the DA-ergic system, which inhibits the DA transporter activity, and Th transcription. Neurochemical effects mediated by GDNF supplement the DA-ergic function, which might play a key role in motor symptoms possibly in pre-clinical or clinical studies.[41,42] In GDNF-transgenic mice, motor neurons are located in the spinal cord; however, GDNF-deficient mice showed a significant decrease in motor neurons. The earlier study by Viglietto et al. shows that GDNF secrets from Sertoli cells to undifferentiated spermatogonia which proves to be a paracrine factor in mouse testes. Moreover, in rodents, proliferation, and suppression of differentiation of undifferentiated spermatogonia are promoted by GDNF.[33,45]
Th and CAs
Th is the rate-limiting enzyme involved in the biosynthesis of CAs, DA, NE, and epinephrine (E) which are the products of pathways that act as neurotransmitters and hormones in the CNS. Growth factors affect CA-ergic differentiation by evidence of Tgf-β, supporting the biosynthesis and expression of CA enzymes which indicate phenotypic expression possibly regulated in the CA-ergic cells, in vitro and in vivo. In female catfish brain, Th and CAs expression levels along with the 5-HT validated that Tph-5-HT[48,49] vis-à vis Th-CA may have a substantial role in brain sex differentiation consequently, on gonads. In vitro, within 24 h treatment of cells with TGF, upsurges significantly the number of Th-positive DA-ergic neurons in rat embryonic day 12; however, neutralization of TGF entirely eradicates the DA-ergic neurons induction. The key molecule, TGF-β, regulates neuronal survival and the Th-CAergic system synergistically with neurotrophic factors, that is, neurotrophin, GDNF, Gfrα-1, and BDNF.[6,30] Our previous study revealed that certain brain-related genes including th, tph, and cyp19a1b possibly have a key role in brain sex differentiation orchestration which regulates gonadal development. The Intrastriatal GDNF target GDNF signaling which protect DA-ergic neuron content and Th activity in postnatal rats. Taken together, affected DA-ergic neurons induce depletion of Th and DA also causing neurodegeneration in the brain and impairment of reproduction partially in catfish supported by the evidence of lower expression level sex steroids and gonad-related genes (Unpublished).
Sex steroid and GnRH
Sex steroids are essential in sexual functions and regulating many neuroendocrine activities. Our recent study highlighted the controlled release of sex steroids through an osmotic pump intraperitoneally implanted with E2 and MT as opposed to the gender-regulated differential GnRH-GTH axis and CA-ergic system. In addition, sex steroid treatment control CA-ergic activity and expression of brain-related genes, that is, catfish GnRH1, Gfrα-1, hsd3b, cyp19a1b, tph, and th consequently mismatched treatment of sex steroids showed estrogenic effect over androgenic at a lower dose which altered reproductive activity at the level of the brain by targeting CAs and GnRH1 in catfish [Figure 1]. The teleost brain produces several neurosteroids such as E2 and neurotrophic factors, that is, GDNF, BDNF, and other neurotransmitters involved in DA neuron development also maintenance of the nervous system and reproduction. In the previous study, sex steroids play a pivotal role during sexual differentiation[52,53] where DA action modulated by E2 combinations with enzymes at different levels produced anti-DAergic effects in teleost. The regulatory role of steroids illustrates the interface between sex steroids, neurodegeneration, regeneration, and neuroinflammation through neurogenesis. Besides, sex steroids regulate the morphology and many neural cells such as neuronal cells, glial cells, and endothelial cells which modulate neural activity, growth factor expression, and their function at the level of the brain in mammals and teleost.[18,54,] A previous study reported that in the nucleus through estrogen receptors (ERs) activity, E2 directly controls transcription at the promoter region of various growth factors, BDNF, TGF-α, and NT-4. Instead, in the dendritic spines, sex steroids can bind androgen receptors and ERs to develop translation of BDNF through MAPK/ ERK and PI3K/AKT activation.[55,56] It has been reported that the brain is influenced by sex hormones T, E, and progesterone; moreover, the nervous system has receptors for sex hormones during fetal development.[57,58] In mice, both prenatal and postnatal administration of non-steroidal antiandrogen (flutamide), T affected sexually dimorphic nuclei development in the hypothalamus. In some species including catfish, sex steroids modulate the secretion of GTH which affects the activity of DA neuron in POA and HYP.[16,60,61] These variations influence the collaboration of gonadal steroids with CAs and GnRH in regulating GTH-II secretion.
CONCLUSION AND FUTURE RESEARCH PERSPECTIVES
This review concludes that the growth factor Tgf-β with coordination of sex steroids and other crucial factors GDNF has a significant impact to regulate brain and gonadal functions by targeting DA-ergic neurons and signaling. Moreover, TGF-β immunolocalization protein expression in the POA-HYP and higher expression in the developing brain by tissue distribution and ontogeny exhibited its possible role in brain development through GnRH and GTH axis, plausibly supporting gonadal functions in catfish. In addition, administration of sex steroid E2 in male catfishes through osmotic pump caused elevated expression of GnRH1 along with CAs resulting in estrogenic impact, whereas MT treated of opposed sex resulted in reverse, although gonadal function yet to study in depth. Importantly, plausible mechanisms of TGF-β with coordination of neurotrophic factors predominantly GDNF/Gfrα-1 and sex steroids, also their manifest neurotrophic effects on midbrain DA-ergic neurons raise expectations for a therapeutic approach to neurological diseases and impairment of reproduction.
MSK is grateful to A Grant-in-Aid (SR/WOS-A/LS-303/2017) from the Department of Science and Technology, Government of India, through the Women Scientist Program (WOS-A) which supported this work completely. MSK is thankful to Professor B. Senthilkumaran, Department of Animal Biology, the University of Hyderabad for providing laboratory facilities and guidance.
Declaration of patient consent
Patient’s consent not required as there are no patients in this study.
Financial support and sponsorship
Department of Science and Technology (DST).
Conflicts of interest
There are no conflicts of interest.
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