Genetic manipulation of teleost endocrine systems started with transgenic overexpression of pituitary growth hormone. Such strategies enhance growth and reduce fertility, but the fish still breed. ...Genome editing using transcription activator-like effector nuclease in zebrafish and medaka has established the role of follicle stimulating hormone for gonadal development and luteinizing hormone for ovulation. Attempts to genetically manipulate the hypophysiotropic neuropeptidergic systems have been less successful. Overexpression of a gonadotropin-releasing hormone (
) antisense in common carp delays puberty but does not block reproduction. Knockout of Gnrh in zebrafish does not impact either sex, while in medaka this blocks ovulation in females without affecting males. Spawning success is not reduced by knockout of the kisspeptins and receptors, agouti-related protein, agouti signaling peptide or spexin. Hypotheses for the lack of effect of these genome edits are presented. Over evolutionary time, teleosts have lost the median eminence typical of mammals. There is consequently direct innervation of gonadotrophs, with the possibility of independent regulation by >20 neurohormones. Removal of a few may have minimal impact. Neuropeptide knockout could leave co-expressed stimulators of gonadotropins functionally intact. Genetic compensation in response to loss of protein function may maintain sufficient reproduction. The species differences in hypothalamo-hypophysial anatomy could be an example of compensation over the evolutionary timescale as teleosts diversified and adapted to new ecological niches. The key neuropeptidergic systems controlling teleost reproduction remain to be uncovered. Classical neurotransmitters are also regulators of luteinizing hormone release, but have yet to be targeted by genome editing. Their essentiality for reproduction should also be explored.
The vertebrate pituitary is arguably one of the most complex endocrine glands from the evolutionary, anatomical and functional perspectives. The pituitary plays a master role in endocrine physiology ...for the control of growth, metabolism, reproduction, water balance, and the stress response, among many other key processes. The synthesis and secretion of pituitary hormones are under the control of neurohormones produced by the hypothalamus. Under this conceptual framework, the communication between the hypophysiotropic brain and the pituitary gland is at the foundation of our understanding of endocrinology. The anatomy of the connections between the hypothalamus and the pituitary gland has been described in different vertebrate classes, revealing diverse modes of communication together with varying degrees of complexity. In this context, the evolution and variation in the neuronal, neurohemal, endocrine and paracrine modes will be reviewed in light of recent discoveries, and a re-evaluation of earlier observations. There appears to be three main hypothalamo-pituitary communication systems: 1. Diffusion, best exemplified by the agnathans; 2. Direct innervation of the adenohypophysis, which is most developed in teleost fish, and 3. The median eminence/portal blood vessel system, most conspicuously developed in tetrapods, showing also considerable variation between classes. Upon this basic classification, there exists various combinations possible, giving rise to taxon and species-specific, multimodal control over major physiological processes. Intrapituitary paracrine regulation and communication between folliculostellate cells and endocrine cells are additional processes of major importance. Thus, a more complex evolutionary picture of hypothalamo-hypophysial communication is emerging. There is currently little direct evidence to suggest which neuroendocrine genes may control the evolution of one communication system versus another. However, studies at the developmental and intergenerational timescales implicate several genes in the angiogenesis and axonal guidance pathways that may be important.
•In teleost fish hypophysiotropic Gnrh neurons do not express Kisspeptin receptors.•gnrh mutants and those with triple gnrh3/2 kiss mutations can reproduce.•In these fish, a compensatory response ...appears to maintain reproduction.•Kiss, Gnrh and other neuropeptides interact to regulate fish reproduction.
It is well known that gonadotropin-releasing hormone (Gnrh) has a key role in reproduction by regulating the synthesis and release of gonadotropins from the anterior pituitary gland of all vertebrates. About 25 years ago, another neuropeptide, kisspeptin (Kiss1) was discovered as a metastasis suppressor of melanoma cell lines and then found to be essential for mammalian reproduction as a stimulator of hypothalamic Gnrh and regulator of puberty onset. Soon after, a kisspeptin receptor (kissr) was found in the teleost brain. Nowadays, it is known that in most teleosts the kisspeptin system is composed of two ligands, kiss1 and kiss2, and two receptors, kiss2r and kiss3r. Even though both kisspeptin peptides, Kiss1 and Kiss2, have been demonstrated to stimulate gonadotropin synthesis and secretion in different fish species, their actions appear not to be mediated by Gnrh neurons as in mammalian models. In zebrafish and medaka, at least, hypophysiotropic Gnrh neurons do not express Kiss receptors. Furthermore, kisspeptinergic nerve terminals reach luteinizing hormone cells in some fish species, suggesting a direct pituitary action. Recent studies in zebrafish and medaka with targeted mutations of kiss and/or kissr genes reproduce relatively normally. In zebrafish, single gnrh mutants and additionally those having the triple gnrh3 plus 2 kiss mutations can reproduce reasonably well. In these fish, other neuropeptides known to affect gonadotropin secretion were up regulated, suggesting that they may be involved in compensatory responses to maintain reproductive processes. In this context, the present review explores and presents different possibilities of interactions between Kiss, Gnrh and other neuropeptides known to affect reproduction in teleost fish. Our intention is to stimulate a broad discussion on the relative roles of kisspeptin and Gnrh in the control of teleost reproduction.
The luteinizing hormone surge is essential for fertility as it triggers ovulation in females and sperm release in males. We previously reported that secretoneurin-a, a neuropeptide derived from the ...processing of secretogranin-2a (Scg2a), stimulates luteinizing hormone release, suggesting a role in reproduction. Here we provide evidence that mutation of the scg2a and scg2b genes using TALENs in zebrafish reduces sexual behavior, ovulation, oviposition, and fertility. Large-scale spawning within-line crossings (n = 82 to 101) were conducted. Wild-type (WT) males paired with WT females successfully spawned in 62%of the breeding trials. Spawning success was reduced to 37% (P = 0.006), 44% (P = 0.0169), and 6% (P < 0.0001) for scg2a−/−, scg2b−/−
, and scg2a−/−;scg2b−/−
mutants, respectively. Comprehensive video analysis indicates that scg2a−/−;scg2b−/−
mutation reduces all male courtship behaviors. Spawning success was 47% in saline-injected WT controls compared to 11% in saline-injected scg2a−/−;scg2b−/−
double mutants. For these mutants, spawning success increased 3-fold following a single intraperitoneal (i.p.) injection of synthetic secretoneurin-a (P = 0.0403) and increased 3.5-fold with injection of human chorionic gonadotropin (hCG). Embryonic survival at 24 h remained on average lower in scg2a−/−;scg2b−/−
fish compared to WT injected with secretoneurin-a (P < 0.001). Significant reductions in the expression of gonadotropin-releasing hormone 3 in the hypothalamus, and luteinizing hormone beta and glycoprotein alpha subunits in the pituitary provide evidence for disrupted hypothalamo-pituitary function in scg2a and scg2b mutant fish. Our results indicate that secretogranin-2 is required for optimal reproductive function and support the hypothesis that secretoneurin is a reproductive hormone.
Highlights • Thyroid hormones (THs) can affect gonadal development and maturation. • THs regulate sex steroid synthesis enzymes in the brain and gonad. • A TH system (including receptors and enzymes) ...is present in vertebrate brains and gonads.
Aromatase (Cyp19a1) is the steroidogenic enzyme that converts androgens into bioactive estrogens, and hence is in a pivotal position to mediate reproduction and sexual behavior. In teleosts, there ...are two aromatase paralogs:
that is highly expressed in granulosa and Leydig cells in the gonads with critical function in sexual differentiation of the ovary, and
that is highly expressed in radial glial cells in the brain with unknown roles in reproduction.
mutant zebrafish lines were used to investigate the importance of the
paralogs for spawning behavior and offspring survival and early development. Mutation of
was found to increase the latency to the first oviposition in females. Mutation of
in females also increased the number of eggs spawned; however, significantly more progeny died during early development resulting in no net increase in female fecundity. This finding suggests a higher metabolic cost of reproduction in
mutant females. In males, the combined mutation of both
paralogs resulted in significantly lower progeny survival rates, indicating a critical function of
during early larval development. These data establish the specific importance of
for female spawning behavior and the importance of the
paralogs for early larval survival.
Highlights • Spawning requires the timed surge of luteinizing hormone from the pituitary. • This is controlled by GnRH and many emerging neuropeptides and pituitary factors. • Knowledge of ...neuroendocrine mechanisms has applications in amphibian conservation.
Sex steroid hormones are synthesized from cholesterol and exert pleiotropic effects notably in the central nervous system. Pioneering studies from Baulieu and colleagues have suggested that steroids ...are also locally-synthesized in the brain. Such steroids, called neurosteroids, can rapidly modulate neuronal excitability and functions, brain plasticity, and behavior. Accumulating data obtained on a wide variety of species demonstrate that neurosteroidogenesis is an evolutionary conserved feature across fish, birds, and mammals. In this review, we will first document neurosteroidogenesis and steroid signaling for estrogens, progestagens, and androgens in the brain of teleost fish, birds, and mammals. We will next consider the effects of sex steroids in homeostatic and regenerative neurogenesis, in neuroprotection, and in sexual behaviors. In a last part, we will discuss the transport of steroids and lipoproteins from the periphery within the brain (and vice-versa) and document their effects on the blood-brain barrier (BBB) permeability and on neuroprotection. We will emphasize the potential interaction between lipoproteins and sex steroids, addressing the beneficial effects of steroids and lipoproteins, particularly HDL-cholesterol, against the breakdown of the BBB reported to occur during brain ischemic stroke. We will consequently highlight the potential anti-inflammatory, anti-oxidant, and neuroprotective properties of sex steroid and lipoproteins, these latest improving cholesterol and steroid ester transport within the brain after insults.
N
-methyladenosine (m
A), catalyzed by Mettl3 methyltransferase, is a highly conserved epigenetic modification in eukaryotic messenger RNA (mRNA). Previous studies have implicated m
A modification in ...multiple biological processes, but the
function of m
A has been difficult to study, because
mutants are embryonic lethal in both mammals and plants. In this study, we have used transcription activator-like effector nucleases and generated viable zygotic
mutant, Z
, in zebrafish. We find that the oocytes in Z
adult females are stalled in early development and the ratio of full-grown stage (FG) follicles is significantly lower than that of wild type. Human chorionic gonadotropin-induced ovarian germinal vesicle breakdown
and the numbers of eggs ovulated
are both decreased as well, while the defects of oocyte maturation can be rescued by sex hormone
and
In Z
adult males, we find defects in sperm maturation and sperm motility is significantly reduced. Further study shows that 11-ketotestosterone (11-KT) and 17β-estradiol (E2) levels are significantly decreased in Z
, and defective gamete maturation is accompanied by decreased overall m
A modification levels and disrupted expression of genes critical for sex hormone synthesis and gonadotropin signaling in Z
Thus, our study provides the first
evidence that loss of Mettl3 leads to failed gamete maturation and significantly reduced fertility in zebrafish. Mettl3 and m
A modifications are essential for optimal reproduction in vertebrates.
PDF
