The Drosophila fruitless (fru) gene encodes a set of putative transcription factors that promote male sexual behavior by controlling the development of sexually dimorphic neuronal circuitry. However, the mechanism whereby fru establishes the sexual fate of neurons remains enigmatic. Here, we show that Fru forms a complex with the transcriptional cofactor Bonus (Bon), which, in turn, recruits either of two chromatin regulators, Histone deacetylase 1 (HDAC1), which masculinizes individual sexually dimorphic neurons, or Heterochromatin protein 1a (HP1a), which demasculinizes them. Manipulations of HDAC1 or HP1a expression change the proportion of male-typical neurons and female-typical neurons rather than producing neurons with intersexual characteristics, indicating that on a single neuron level, this sexual switch operates in an all-or-none manner.

The Drosophila fruitless (fru) gene is regarded as a master regulator of the formation of male courtship circuitry, yet little is known about its molecular basis of action. We show that roundabout 1 (robo1) knockdown in females promotes formation of the male-specific neurite in sexually dimorphic mAL interneurons and that overexpression of the male-specific Fru(BM) diminishes the expression of Robo1 in the fly brain. Our electrophoretic mobility shift and reporter assays identify the 42-bp segment encompassing the palindrome sequence T T C G C T G C G C C G T G A A in the 5' UTR of robo1 exon1 as the Fru(BM)-responsive element. We find that ∼10-bp deletions in the palindrome sequence induce a loss of the male-specific neurite and disrupt male courtship patterns. This study paves the way for a thorough understanding of the mechanism whereby Fru proteins orchestrate transcription for the formation of courtship circuitry.

Pattern formation along the proximal-distal (PD) axis in the developing limb bud serves as a good model for learning how cell fate and regionalization of domains, which are essential processes in morphogenesis during development, are specified by positional information. In the present study, detailed fate maps for the limb bud of the chick embryo were constructed in order to gain insights into how cell fate for future structures along the PD axis is specified and subdivided. Our fate map revealed that there is a large overlap between the prospective autopod and zeugopod in the distal limb bud at an early stage (stage 19), whereas a limb bud at this stage has already regionalized the proximal compartments for the prospective stylopod and zeugopod. A clearer boundary of cell fate specifying the prospective autopod and zeugopod could be seen at stage 23, but cell mixing was still detectable inside the prospective autopod region at this stage. Detailed analysis of HOXA11 AND HOXA13 expression at single cell resolution suggested that the cell mixing is not due to separation of some different cell populations existing in a mosaic. Our findings suggest that a mixable unregionalized cell population is maintained in the distal area of the limb bud, while the proximal region starts to be regionalized at the early stage of limb development.

It remains an enigma how the nervous system of different animal species produces different behaviors. We studied the neural circuitry for mating behavior in , a species that displays unique courtship actions not shared by other members of the genera including the genetic model, in which the core courtship circuitry has been identified. We disrupted the () gene, a master regulator for the courtship circuitry formation in , resulting in complete loss of mating behavior. We also generated , which expresses the optogenetic activator Chrimson fused with a fluorescent marker under the native promoter. The-labeled circuitry in visualized by revealed differences between females and males, optogenetic activation of which in males induced mating behavior including attempted copulation. These findings provide a substrate for neurogenetic dissection and manipulation of behavior in non-model animals, and will help to elucidate the neural basis for behavioral diversification. How did behavioral specificity arise during evolution? Here we attempted to address this question by comparing the parallel genetically definable neural circuits controlling the courtship behavior of , a genetic model, and its relative,, which exhibits a courtship behavioral pattern unique to it, including nuptial gift transfer. We found that the circuit, which is required for male courtship behavior, was slightly but clearly different from its counterpart, and that optogenetic activation of this circuit induced -specific behavior, i.e., regurgitating crop contents, a key element of transfer of nuptial gift. Our study will pave the way for determining how and which distinctive cellular elements within the circuit determine the species-specific differences in courtship behavior.

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In Drosophila, some neurons develop sex-specific neurites that contribute to dimorphic circuits for sex-specific behavior. As opposed to the idea that the sexual dichotomy in transcriptional profiles produced by a sex-specific factor underlies such sex differences, we discovered that the sex-specific cleavage confers the activity as a sexual-fate inducer on the pleiotropic transcription factor Longitudinals lacking (Lola). Surprisingly, Fruitless, another transcription factor with a master regulator role for courtship circuitry formation, directly binds to Lola to protect its cleavage in males. We also show that Lola cleavage involves E3 ubiquitin ligase Cullin1 and 26S proteasome. Our work adds a new dimension to the study of sex-specific behavior and its circuit basis by unveiling a mechanistic link between proteolysis and the sexually dimorphic patterning of circuits. Our findings may also provide new insights into potential causes of the sex-biased incidence of some neuropsychiatric diseases and inspire novel therapeutic approaches to such disorders.

Neurogenetic analyses in the fruit fly Drosophila melanogaster revealed that gendered behaviors, including courtship, are underpinned by sexually dimorphic neural circuitries, whose development is directed in a sex-specific manner by transcription factor genes, fruitless (fru) and doublesex (dsx), two core members composing the sex-determination cascade. Via chromatin modification the Fru proteins translated specifically in the male nervous system lead the fru-expressing neurons to take on the male fate, as manifested by their male-specific survival or male-specific neurite formations. One such male-specific neuron group, P1, was shown to be activated when the male taps the female abdomen. Moreover, when artificially activated, P1 neurons are sufficient to induce the entire repertoire of the male courtship ritual. These studies provide a conceptual framework for understanding how the genetic code for innate behavior can be embodied in the neuronal substrate.

To determine the relationship between premature ovarian failure (POF) and skewed X-chromosome inactivation (XCI), karyotype, and XCI status in 43 patients with POF (group I) and 43 age-matched control women with regular menstrual cycles (group II) were evaluated. Evaluation of XCI status was based on the CAG triplet repeat polymorphism assay in the androgen receptor gene after sodium bisulfite treatment of DNA samples, and XCI patterns were classified as random (XCI < 70% skewing) or skewed (> or =70%). Furthermore, skewed XCI was classified under three different thresholds (> or =70, > or =80, or > or =90%). Karyotyping by G-banding and fluorescence in situ hybridization (FISH) on peripheral blood lymphocytes showed that one patient in group I had a deletion of Xq22, and another was 47,XXX. The frequency of low-level 45,X/46,XX mosaicism was nearly equal in both groups. In women without any X-chromosomal aberrations, the incidence of skewed XCI in group I was significantly higher than in group II on all threshold levels. Furthermore, extremely skewed XCI (> or =90%) was observed only in group I. These results indicate that POF may be caused by some underlying genetic disorders, which may induce skewed XCI.