Implicating transforming growth factor-β and sex steroids in the regulation of brain-gonadal functions

INTRODUCTION

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.^[3] 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).^[4] 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^[7] such as stimulation of follicular development and steroid hormone 17β-estradiol (E₂) and androgen (T) production in mammals.^[8] In rainbow trout, Tgf-β stimulates the proliferation of spermatogonial and primordial germ cells^[9] 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.^[15] 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.^[16] 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.^[19] 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.^[22] McEwen^[23] 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

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].^[18] 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.^[19] The regulatory role of steroids illustrates the interface between sex steroids, neurodegeneration, regeneration, and neuroinflammation through neurogenesis.^[54] 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.^[59] 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.^[21]

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Figure 1:

The schematic diagram represented the role of mismatched sex steroids treatment, drug delivery through an osmotic pump in the male and female brain using the catfish model and overexpression of transcripts/genes and their influences on the brain-gonadal functions. T: Testosterone, 11-KT -E₂: Estradiol-17b, MT: Methyltestosterone, CAs: Catecholamines, gdnf/gfrα-1: Glial cell line-derived neurotrophic factor/gdnf family receptor alpha-1, GnRH1: A gonadotropin-releasing hormone, tph: Tryptophan hydroxylase, th: Tyrosine hydroxylase, Tgf-β: Transforming growth factor-beta, Cyp19a1b: brain aromatase, and hsd3b: 3β-hydroxysteroid dehydrogenase.

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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.