Generic selectors
Exact matches only
Search in title
Search in content
Post Type Selectors
Filter by Categories
Case Series
Commentary
Editorial
Invited Article
Original Article
Review Article
Short Communication
Special Issue on COVID-19 & ART
Generic selectors
Exact matches only
Search in title
Search in content
Post Type Selectors
Filter by Categories
Case Series
Commentary
Editorial
Invited Article
Original Article
Review Article
Short Communication
Special Issue on COVID-19 & ART
View/Download PDF

Translate this page into:

Review Article
2022
:3;
9
doi:
10.25259/JRHM_12_2022

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

Department of Animal Biology, School of Life Sciences, University of Hyderabad, Hyderabad, Telangana, India
Corresponding author: Mamta Sajwan Khatri, Department of Animal Biology, School of Life Sciences, University of Hyderabad, Hyderabad, Telangana, India. mamtasajwan13@gmail.com, mamta@uohyd.ac.in
Licence
This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-Share Alike 4.0 License, which allows others to remix, transform, and build upon the work non-commercially, as long as the author is credited and the new creations are licensed under the identical terms.

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.

Abstract

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.

Keywords

Transforming growth factor-beta
GDNF
Sex steroids
Brain
Gonads
Sexual development

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

Tgf-β

Tgf-β is a crucial growth factor for developing midbrain DAergic neurons in vitro and in vivo.[2] 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.[26] 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.[26] 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.[28] The significance of Tgf-β in reproductive function suggests the implication of cytokines in infertility and other sexual dysfunction.[29] 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.[3]

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[31] 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[37] 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.[6] 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.[34] 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.[43] The earlier study by Viglietto et al.[44] 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.[46] In female catfish brain, Th and CAs expression levels[47] 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.[50] 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.[2] 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.[50] The Intrastriatal GDNF target GDNF signaling which protect DA-ergic neuron content and Th activity in postnatal rats.[51] 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].[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]

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.

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.

Acknowledgment

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.

References

  1. , . Targeted mutations of transforming growth factor-β genes reveal important roles in mouse development and adult homeostasis. Eur J Biochem. 2000;267:6982-8.
    [CrossRef] [PubMed] [Google Scholar]
  2. , , , , . Transforming growth factor-βs are essential for the development of midbrain dopaminergic neurons in vitro and in vivo. J Neurosci. 2003;23:5178-86.
    [CrossRef] [PubMed] [Google Scholar]
  3. , . Transforming growth factor β: Cloning and expression profiling in the brain of catfish model. J Eng Res. 2022;26:23-31.
    [Google Scholar]
  4. , . The role of TGF-β superfamily signaling in neurological disorders. Acta Biochim Biophys Sin. 2018;50:106-20.
    [CrossRef] [PubMed] [Google Scholar]
  5. , , , . TGF-beta superfamily members promote survival of midbrain dopaminergic neurons and protect them against MPP+ toxicity. EMBO J. 1995;14:736-42.
    [CrossRef] [PubMed] [Google Scholar]
  6. , . GDNF family receptor α-1 in catfish: Possible implication to brain dopaminergic activity. Brain Res Bull. 2018;140:270-80.
    [CrossRef] [PubMed] [Google Scholar]
  7. , , , . All in the family: TGF-β family action in testis development. Reproduction. 2006;132:233-46.
    [CrossRef] [PubMed] [Google Scholar]
  8. , . TGF-β superfamily members and ovarian follicle development. Reproduction. 2006;132:191-206.
    [CrossRef] [PubMed] [Google Scholar]
  9. , , , . A novel transforming growth factor-β superfamily member expressed in gonadal somatic cells enhances primordial germ cell and spermatogonial proliferation in rainbow trout (Oncorhynchus mykiss) Dev Biol. 2007;30:266-75.
    [CrossRef] [PubMed] [Google Scholar]
  10. , , , , , . Cloning of transforming growth factor-β1 (TGF-β1) and its Type II receptor from zebrafish ovary and role of TGF-β1 in oocyte maturation. Endocrinology. 2003;144:1931-41.
    [CrossRef] [PubMed] [Google Scholar]
  11. , , . Potential targets of transforming growth factor-beta1 during inhibition of oocyte maturation in zebrafish. Reprod Biol Endocrinol. 2005;3:1-11.
    [CrossRef] [PubMed] [Google Scholar]
  12. , . Defining the actions of transforming growth factor beta in reproduction. Bioessays. 2002;24:904-14.
    [CrossRef] [PubMed] [Google Scholar]
  13. , , , , . TGF-β and the regulation of neuron survival and death. J Physiol Paris. 2002;96:25-30.
    [CrossRef] [PubMed] [Google Scholar]
  14. , , , , . Identification and evolution of TGF-β signaling pathway members in twenty-four animal species and expression in Tilapia. Int J Mol Sci. 2018;19:1154.
    [CrossRef] [PubMed] [Google Scholar]
  15. , , , , , , et al. TGF-β signaling in dopaminergic neurons regulates dendritic growth, excitatory-inhibitory synaptic balance, and reversal learning. Cell Rep. 2016;17:3233-45.
    [CrossRef] [PubMed] [Google Scholar]
  16. . Neuroendocrine regulation of gonadotrophin II release and gonadal growth in the goldfish, Carassius auratus. Rev Rep. 1997;2:55-68.
    [CrossRef] [PubMed] [Google Scholar]
  17. , , . A genetic approach to dissect sexually dimorphic behaviors. Horm Behav. 2008;53:627-37.
    [CrossRef] [PubMed] [Google Scholar]
  18. , , , , . Controlled release of sex steroids through osmotic pump alters brain GnRH1 and catecholaminergic system dimorphically in the catfish, Clarias gariepinus. Brain Res Bull. 2020;164:325-33.
    [CrossRef] [PubMed] [Google Scholar]
  19. , , . Estrogen regulation of gene expression in the brain: A possible mechanism altering the response to psychostimulants in female rats. Mol Brain Res. 2002;100:75-83.
    [CrossRef] [PubMed] [Google Scholar]
  20. , , . Brain regulation of reproduction in teleosts. Bull Inst Zool Acad Sin Monogr. 1991;16:89-118.
    [Google Scholar]
  21. , , . Comparative Endocrinology and Reproduction New Delhi, India: Narousa Publishing House; . p. 113-36.
    [Google Scholar]
  22. , , , , . Developmental and functional effects of steroid hormones on the neuroendocrine axis and spinal cord. J Neuroendocrinol. 2016;28:10.
    [CrossRef] [PubMed] [Google Scholar]
  23. . Gonadal steroid action on brain sexual differentiation and sexual behavior In: , ed. Neurotransmitter Interaction and Compartmentation. Boston, MA: Springer; . p. 651-63.
    [CrossRef] [Google Scholar]
  24. , , . TGF-β receptor Type II deficiency results in defects of yolk sac hematopoiesis and vasculogenesis. Dev Biol. 1996;179:297-302.
    [CrossRef] [PubMed] [Google Scholar]
  25. , , , , , , et al. TGF beta2 knockout mice have multiple developmental defects that are non-overlapping with other TGF beta knockout phenotypes. Development. 1997;124:2659-70.
    [CrossRef] [PubMed] [Google Scholar]
  26. , . Presence of transforming growth factor-beta and their selective cellular localization in human ovarian tissue of various reproductive stages. Endocrinology. 1992;130:1707-15.
    [CrossRef] [PubMed] [Google Scholar]
  27. , . Regulation of TGF-β signal transduction. Scientifica. 2014;23:2014.
    [CrossRef] [PubMed] [Google Scholar]
  28. , , . Activin and transforming growth factor-β as local regulators of ovarian steroidogenesis in the goldfish. Gen Comp Endocrinol. 2003;132:142-50.
    [CrossRef] [PubMed] [Google Scholar]
  29. , , , , , , et al. Molecular characterization and expression analysis of anti-Müllerian hormone in common carp (Cyprinus carpio) adult testes. Gene Expr Patterns. 2021;40:119169.
    [CrossRef] [PubMed] [Google Scholar]
  30. , , , , , , et al. Glial cell line-derived neurotrophic factor requires transforming growth factor-β for exerting its full neurotrophic potential on peripheral and CNS neurons. J Neurosci Res. 1998;18:9822-34.
    [CrossRef] [PubMed] [Google Scholar]
  31. , , . Evolution of the GDNF family ligands and receptors. Brain Behav Evol. 2006;68:181-90.
    [CrossRef] [PubMed] [Google Scholar]
  32. , , , , . Glial cell-line-derived neurotrophic factor-mediated RET signaling regulates spermatogonial stem cell fate. Biol Rep. 2006;74:314-21.
    [CrossRef] [PubMed] [Google Scholar]
  33. , , , , , , et al. GDNF signalling through the Ret receptor tyrosine kinase. Nature. 1996;381:789-93.
    [CrossRef] [PubMed] [Google Scholar]
  34. , . Glial cell line-derived neurotrophic factor gene delivery in Parkinson's disease: A delicate balance between neuroprotection, trophic effects, and unwanted compensatory mechanisms. Front Neuroanat. 2017;11:29.
    [CrossRef] [PubMed] [Google Scholar]
  35. , , . Radial glial cells: Key organisers in CNS development. Int J Biochem Cell Biol. 2014;46:76-9.
    [CrossRef] [PubMed] [Google Scholar]
  36. , , . Radial glial cell: Critical functions and new perspective as a steroid synthetic cell. Gen Comp Endocrinol. 2014;203:181-5.
    [CrossRef] [PubMed] [Google Scholar]
  37. , , , , , , et al. Identification of aromatase-positive radial glial cells as progenitor cells in the ventricular layer of the forebrain in zebrafish. J Comp Neurol. 2007;501:150-67.
    [CrossRef] [PubMed] [Google Scholar]
  38. , , . Role of aromatase and radial glial cells in neurotoxin-induced dopamine neuron degeneration and regeneration. Gen Comp Endocrinol. 2017;241:69-79.
    [CrossRef] [PubMed] [Google Scholar]
  39. , , , , , , et al. GDNF: A potent survival factor for motoneurons present in peripheral nerve and muscle. Science. 1994;266:1062-64.
    [CrossRef] [PubMed] [Google Scholar]
  40. , , , . GDNF prevents degeneration and promotes the phenotype of brain noradrenergic neurons in vivo. Neuron. 1995;15:1465-73.
    [CrossRef] [PubMed] [Google Scholar]
  41. , , , , , , et al. Gene delivery of AAV2-neurturin for Parkinson's disease: A double-blind, randomised, controlled trial. Lancet Neurol. 2010;9:1164-72.
    [CrossRef] [PubMed] [Google Scholar]
  42. , , . Parkinson's disease gene therapy: Success by design meets failure by efficacy. Mol Ther. 2014;22:487-97.
    [CrossRef] [PubMed] [Google Scholar]
  43. , , , , , . Glial cell line-derived neurotrophic factor and developing mammalian motoneurons: Regulation of programmed cell death among motoneuron subtypes. J Neurosci. 2000;20:5001-11.
    [CrossRef] [PubMed] [Google Scholar]
  44. , , , , , , et al. Glial cell line-derived neurotrophic factor and neurturin can act as paracrine growth factors stimulating DNA synthesis of Ret-expressing spermatogonia. Int J Oncol. 2000;16:689-783.
    [CrossRef] [PubMed] [Google Scholar]
  45. , , , , , , et al. Regulation of cell fate decision of undifferentiated spermatogonia by GDNF. Science. 2000;287:1489-93.
    [CrossRef] [PubMed] [Google Scholar]
  46. , . Role of growth factors in catecholaminergic expression by neural crest cells: In vitro effects of transforming growth factor beta1. Dev Dyn. 1993;196:1.
    [CrossRef] [PubMed] [Google Scholar]
  47. , , , , , . Cloning and expression analysis of tyrosine hydroxylase and changes in catecholamine levels in brain during ontogeny and after sex steroid analogues exposure in the catfish, Clarias batrachus. Gen Comp Endocrinol. 2014;197:18-25.
    [CrossRef] [PubMed] [Google Scholar]
  48. , , , , , , et al. Dimorphic expression of tryptophan hydroxylase in the brain of XX and XY Nile tilapia during early development. Gen Comp Endocrinol. 2010;166:320-9.
    [CrossRef] [PubMed] [Google Scholar]
  49. , , , , , . Gender differences in tryptophan hydroxylase-2 mRNA, serotonin, and 5-hydroxytryptophan levels in the brain of catfish, Clarias gariepinus, during sex differentiation. Gen Comp Endocrinol. 2011;171:94-104.
    [CrossRef] [PubMed] [Google Scholar]
  50. , , , , , . "Brain sex differentiation" in teleosts: Emerging concepts with potential biomarkers. Gen Comp Endocrinol. 2015;220:33-40.
    [CrossRef] [PubMed] [Google Scholar]
  51. , , , , , . Intrastriatal glial cell line-derived neurotrophic factors for protecting dopaminergic neurons in the substantia nigra of mice with Parkinson disease. Neural Regen Res. 2007;2:207-10.
    [CrossRef] [Google Scholar]
  52. , , . Induction of XY sex reversal by estrogen involves altered gene expression in a teleost, tilapia. Cytogenet Genome Res. 2003;101:289-94.
    [CrossRef] [PubMed] [Google Scholar]
  53. , , , , . The sensitive period for male-to-female sex reversal begins at the embryonic stage in the Nile tilapia and is associated with the sexual genotype. Mol Rep Dev. 2014;81:1146-58.
    [CrossRef] [PubMed] [Google Scholar]
  54. . Sex steroids, adult neurogenesis, and inflammation in CNS homeostasis, degeneration, and repair. Front Endocrinol. 2018;9:205.
    [CrossRef] [PubMed] [Google Scholar]
  55. , , , , , , et al. Rapid increase of spines by dihydrotestosterone and testosterone in hippocampal neurons: Dependence on synaptic androgen receptor and kinase networks. Brain Res. 2015;1621:121-32.
    [CrossRef] [PubMed] [Google Scholar]
  56. , . Estrogen receptor protein interaction with phosphatidylinositol 3-kinase leads to activation of phosphorylated Akt and extracellular signal-regulated kinase 1/2 in the same population of cortical neurons: A unified mechanism of estrogen action. J Neurosci. 2006;26:9439-47.
    [CrossRef] [PubMed] [Google Scholar]
  57. , . The effects of prenatal sex steroid hormones on sexual differentiation of the brain. J Turk Ger Gynecol Assoc. 2013;14:163.
    [CrossRef] [PubMed] [Google Scholar]
  58. , . Maternal hormonal milieu influence on fetal brain development. Brain Behav. 2018;8:e00920.
    [CrossRef] [PubMed] [Google Scholar]
  59. , , , . Pre-or postnatal testosterone and flutamide effects on sexually dimorphic nuclei of the rat hypothalamus. Dev Brain Res. 2000;120:261-6.
    [CrossRef] [PubMed] [Google Scholar]
  60. , . Dopaminergic regulation of brain gonadotropin-releasing hormone in male goldfish during spawning behavior. Neuroendocrinology. 1990;52:276-83.
    [CrossRef] [PubMed] [Google Scholar]
  61. , . Changes in hypothalamic catecholamines, dopamine-β-hydroxylase, and phenylethanolamine-N-methyltransferase in the catfish Heteropneustes fossilis in relation to season, raised photoperiod and temperature, ovariectomy, and estradiol-17β replacement. Gen Comp Endocrinol. 1995;97:121-34.
    [CrossRef] [PubMed] [Google Scholar]
Show Sections