Biology subjects

Okubo, K.

Publications and source records attributed to Okubo, K..

10 recordsLinked to original sources

bioRxiv2024

Neuroestrogens facilitate male-typical behaviors by potentiating androgen receptor signaling in medaka

In rodents, estrogens aromatized from androgens in the brain are essential for the development of male-typical behaviors. In many other vertebrates including humans and teleost fish, however, androgens facilitate these behaviors directly via the androgen receptor without aromatization into estrogens. Here we report that mutagenesis-derived male medaka fish lacking Cyp19a1b (a subtype of aromatase predominantly expressed in the brain) exhibit severely impaired male-typical mating and aggression, despite elevated brain androgen levels. These phenotypes can be rescued by estrogen administration, indicating that brain-derived estrogens are pivotal for male-typical behaviors even in teleosts. Our results further suggest that these estrogens facilitate male-typical behaviors by potentiating androgen action in the brain via the direct stimulation of androgen receptor transcription. Taken together, these findings reveal a previously unappreciated mode of action of brain-derived estrogens in shaping male-typical behaviors.

physiology↗

bioRxiv2024

The decision of male medaka to mate or fight depends on two complementary androgen signaling pathways

Adult male animals typically court and attempt to mate with females, while attacking other males. Emerging evidence from mice indicates that neurons expressing the estrogen receptor ESR1 in behaviorally relevant brain regions play a central role in mediating these mutually exclusive behavioral responses to conspecifics. However, the findings in mice are unlikely to apply to most other vertebrates, where androgens -- rather than estrogens -- have been implicated in male behaviors. Here we report that male medaka (Oryzias latipes) lacking one of the two androgen receptor subtypes (Ara) are less aggressive toward other males and instead actively court them, while those lacking the other subtype (Arb) are less motivated to mate with females and conversely attack them. These findings indicate that, in male medaka, the Ara- and Arb-mediated androgen signaling pathways facilitate appropriate behavioral responses, while simultaneously suppressing inappropriate responses, to males and females, respectively. Notably, males lacking either receptor retain the ability to discriminate the sex of conspecifics, suggesting a defect in the subsequent decision-making process to mate or fight. We further show that Ara and Arb are expressed in intermingled but largely distinct populations of neurons, and stimulate the expression of different behaviorally relevant genes including galanin and vasotocin, respectively. Collectively, our results demonstrate that male teleosts make adaptive decisions to mate or fight as a result of the activation of one of two complementary androgen signaling pathways, depending on the sex of the conspecific that they encounter.

physiology↗

bioRxiv2023

Male-specific vasotocin expression in the medaka tuberal hypothalamus: androgen dependence and probable role in aggression

Terrestrial vertebrates have a population of androgen-dependent vasotocin (VT)-expressing neurons in the extended amygdala that are more abundant in males and mediate male-typical social behaviors, including aggression. Teleosts lack these neurons but instead have novel male-specific VT-expressing neurons in the tuberal hypothalamus. Here we found in medaka that vt expression in these neurons is dependent on post-pubertal gonadal androgens and that androgens can act on these neurons to directly stimulate vt transcription via the androgen receptor subtype Ara. Furthermore, administration of exogenous VT induced aggression in females and alterations in the androgen milieu led to correlated changes in the levels of tuberal hypothalamic vt expression and aggression in both sexes. However, genetic ablation of vt failed to prevent androgen-induced aggression in females. Collectively, our results demonstrate a marked androgen dependence of male-specific vt expression in the teleost tuberal hypothalamus, although its relevance to male-typical aggression needs to be further validated.

neuroscience↗

bioRxiv2023

Cholecystokinin is the follicle-stimulating hormone (FSH)-releasing hormone

In vertebrates, folliculogenesis and ovulation are regulated by two distinct pituitary gonadotropins: follicle-stimulating hormone (FSH) and luteinizing hormone (LH). Today, there is an intriguing consensus that a single hypothalamic neurohormone, gonadotropin-releasing hormone (GnRH), regulates the secretion of both FSH and LH, although the required timing and functions of FSH and LH are different. However, recent studies in vertebrates other than mammals indicate that the effect of GnRH on FSH is too weak to explain its regulation. Therefore, to challenge this "solo GnRH model," we aimed to identify the other gonadotropin regulator, FSH-releasing hormone (FSH-RH), in vertebrates. Here, by using the model teleost medaka, we successfully identified cholecystokinin as the FSH-RH. Our histological and in vitro analyses demonstrated that hypothalamic cholecystokinin-expressing neurons directly affect FSH cells through the cholecystokinin receptor, Cckbr1, thereby increasing the expression and release of FSH. Remarkably, the knockout of cholecystokinin ligand or cckbr1 minimized FSH expression and resulted in a complete failure of folliculogenesis. Our results challenge the longstanding consensus of the solo GnRH model in all vertebrates; instead, we propose the existence of a "dual GnRH model" group in vertebrates that utilizes both FSH-RH and LH-RH. The discovery of the FSH-RH in vertebrates opens not only a new era in neuroendocrinology but also possible applications involving vertebrate reproduction.

neuroscience↗

bioRxiv2022

Comprehensive analysis of gene regulatory dynamics, fitness landscape, and population evolution during sexual reproduction

The fitness landscape is a critical concept in evolutionary biology and genetics that depicts fitness in the genotype space and visualizes the relationship between genotype and fitness. However, the fitness landscape is challenging to characterize because the quantitative relationships between genotype and phenotype and their association to fitness has not been comprehensively well described. To address this challenge, we adopted gene regulatory networks to determine gene expression dynamics. We analyzed how phenotype and fitness are shaped by the genotype in two-gene networks. A two-by-two matrix provided the two-gene regulatory network in which a vector with two angle values ({Theta}) was introduced to characterize the genotype. Mapping from this angle vector to phenotypes allowed for the classification of steady-state expression patterns of genes into seven types. We then studied all possible fitness functions given by the Boolean output from the on/off expression of the two genes. The possible fitness landscapes were obtained as a function of the genetic parameters {Theta}. Finally, the evolution of the population distribution under sexual reproduction was investigated in the obtained landscape. We found that the distribution was restricted to a convex region within the landscape, resulting in the branching of population distribution, including the speciation process.

evolutionary biology↗

bioRxiv2022

Allogeneic testes transplanted into castrated adult medaka (Oryzias latipes) are engrafted and can function over a long period for production of donor-derived offspring by natural mating

Generally, successful testis transplantation has been considered to require immune suppression in the recipient to avoid rejection of the transplanted tissue. In the present study, we demonstrate in medaka that allogeneic adult testicular tissue will engraft in adult recipients immediately after partial castration without the use of immunosuppressive drugs. The allografted testes are retained in the recipients body for at least three months and are able to produce viable sperm that yield offspring after natural mating. Some recipients showed a high frequency (over 60%) of offspring derived from spermatozoa produced by the transplanted testicular tissue. Histological analyses showed that allografted testicular tissues included both germ cells and somatic cells that had established within an immunocompetent recipient testis. The relative simplicity of this testis transplantation approach will benefit investigations of the basic processes of reproductive immunology and will improve the technique of gonadal tissue transplantation.

zoology↗

bioRxiv2021

Heterosis Related to Fitness and Phenotypic Variance in the Evolution of Diploid Gene Regulatory Network

Heterosis describes the phenomenon whereby a hybrid population has higher fitness than an inbred population, and has previously been explained by either Mendelian dominance or overdominance, where it is generally assumed that one gene controls one trait. How-ever, recent studies have demonstrated that genes interact through a complex gene regulatory network (GRN). Furthermore, phenotypic variance due to noise is reportedly lower for heterozygotes, whereas the origin of such variance-related heterosis remains elusive. There-fore, a theoretical analysis linking heterosis to GRN evolution and stochastic gene expression dynamics is required. Here, we investigate heterosis related to fitness and phenotypic variance in a system with interacting genes, by numerically evolving diploid GRNs. According to the results, the heterozygote population exhibited higher fitness than the homozygote population, that is, fitness-related heterosis resulting from evolution. In addition, the heterozygote population expressed lower noise-related phenotypic variance in expression levels than the homozygous population, implying that the heterozygote population is more robust to noise. Furthermore, the distribution of the ratio of heterozygote phenotypic variance to homozygote phenotypic variance exhibited quantitative agreement with previous experimental results. By applying dominance and over-dominance to the gene expression pattern rather than only a single gene expression, we confirmed the correlation between heterosis and overdominance. We explain our results by proposing that the convex high-fitness region is evolutionarily shaped in the genetic space to gain noise robustness under genetic mixing through sexual reproduction. Significance StatementHeterosis, that is higher fitness in hybrid populations than inbred populations, is a long-standing problem in genetics, evolution, and breeding studies. Heterosis is not necessarily the result of a trait uniquely determined by a single gene, but likely involves stochasticity and interactions among genes. Through numerical evolution of the gene regulatory network, we demonstrate that heterosis is shaped by evolution to achieve robustness against noise and genetic mixing by sexual recombination in gene expression dynamics. That is, a mixed population is more robust to noise than inbred populations, as revealed experimentally by reduced phenotypic variance. The observed link between heterosis and phenotypic robustness, Mendelian dominance, and the convex single-humped fitness landscape represents a novel avenue in evolution and genetics research.

evolutionary biology↗

bioRxiv2021

Balanced release of neuropeptide FF and gonadotropin-releasing hormone 3 modulates male sexual behavior

Animals properly perform sexual behaviors by using multiple sensory cues. However, neural mechanisms integrating multiple sensory cues and regulating motivation for sexual behaviors remain unclear. Here, we focused on peptidergic neurons, terminal nerve gonadotropin-releasing hormone (TN-GnRH) neurons, which receive inputs from various sensory systems and co-express neuropeptide FF (NPFF) in addition to GnRH. Our behavioral analyses using knockout medaka of GnRH (gnrh3) and/or NPFF (npff) demonstrated that some sexual behavioral repertories were delayed, not disrupted, in gnrh3-/- and npff-/- males, while the double knockout showed normal behaviors. We also found anatomical evidence to show that both neuropeptides modulate the sexual behavior-controlling brain areas. Furthermore, we demonstrated that NPFF activates neurons in the preoptic area via indirect pathway, which is considered to induce the increase in the motivation for male sexual behaviors. Considering these results, we propose a novel mechanism by which balanced release of co-existing peptides is important for the neuromodulatory function of TN-GnRH neurons in the control of behavioral motivation. Our results may go a long way toward understanding the functional significance of peptidergic neuromodulation in response to external environments.

neuroscience↗

bioRxiv2021

Evolution of Mendelian dominance in gene regulatory networks associated with phenotypic robustness

Mendelian inheritance is a fundamental law of genetics. Considering two alleles in a diploid, a phenotype of a heterotype is dominated by a particular homotype according to the law of dominance. This picture is usually based on simple genotype-phenotype mapping in which one gene regulates one phenotype. However, in reality, some interactions between genes can result in deviation from Mendelian dominance. Here, by using the numerical evolution of diploid gene regulatory networks (GRNs), we discuss whether Mendelian dominance evolves beyond the classical case of one-to-one genotype-phenotype mapping. We examine whether complex genotype-phenotype mapping can achieve Mendelian dominance through the evolution of the GRN with interacting genes. Specifically, we extend the GRN model to a diploid case, in which two GRN matrices are added to give gene expression dynamics, and simulate evolution with meiosis and recombination. Our results reveal that Mendelian dominance evolves even under complex genotype-phenotype mapping. This dominance is achieved via a group of genotypes that differ from each other but have a common phenotype given by the expression of target genes. Calculating the degree of dominance shows that it increases through the evolution, correlating closely with the decrease in phenotypic fluctuations and the increase in robustness to initial noise. This evolution of Mendelian dominance is associated with phenotypic robustness against meiosis-induced genome mixing, whereas sexual recombination arising from the mixing of chromosomes from the parents further enhances dominance and robustness. Owing to this dominance, the robustness to genetic differences increases, while the optimal fitness is sustained up to a large difference between the two genomes. In summary, Mendelian dominance is achieved by groups of genotypes that are associated with the increase in phenotypic robustness to noise. Author summaryMendelian dominance is one of the most fundamental laws in genetics. When two conflicting characters occur in a single diploid, the dominant character is always chosen. Assuming that one gene makes one character, this law is simple to grasp. However, in reality, phenotypes are generated via interactions between several genes, which may alter Mendels dominance law. The evolution of robustness to noise and mutations has been investigated extensively using complex expression dynamics with gene regulatory networks. Here, we applied gene-expression dynamics with complex interactions to the case of a diploid and simulated the evolution of the gene regulatory network to generate the optimal phenotype given by a certain gene expression pattern. Interestingly, after evolution, Mendelian dominance is achieved via a group of genes. This group-based Mendelian dominance is shaped by phenotype insensitivity to genome mixing by meiosis and evolves concurrently with the robustness to noise. By focusing on the influence of phenotypic robustness, which has received considerable attention recently, our result provides a novel perspective as to why Mendels law of dominance is commonly observed.

evolutionary biology↗

bioRxiv2019

Neuropeptide B mediates female sexual receptivity in medaka fish, acting in a female-specific but reversible manner

Male and female animals display innate sex-specific mating behaviors. Among vertebrates, teleosts are unique in that altering the adult sex steroid milieu can reverse sex-typical mating behaviors, suggesting sexual lability of their brains. In the teleost medaka, neuropeptide B (NPB) is expressed female-specifically in the brain nuclei implicated in mating behavior. Here, we demonstrate that NPB is a direct mediator of estrogen action on female mating behavior, acting in a female-specific but reversible manner. Analysis of regulatory mechanisms revealed that the female-specific expression of NPB is dependent on direct transcriptional activation by estrogen via an estrogen-responsive element and is reversed in response to changes in the adult sex steroid milieu. Behavioral studies of NPB knockouts revealed that female-specific NBP mediates female receptivity to male courtship. The female-specific NPB signaling identified herein is presumably a critical element of the neural circuitry underlying sexual dimorphism and lability of mating behaviors in teleosts.

neuroscience↗