Large-scale meta-analysis highlights the hypothalamic–pituitary–gonadal axis in the genetic regulation of menstrual cycle length

The normal menstrual cycle requires a delicate interplay between the hypothalamus, pituitary and ovary. Therefore, its length is an important indicator of female reproductive health. Menstrual cycle length has been shown to be partially controlled by genetic factors, especially in the follicle-stimulating hormone beta-subunit (FSHB) locus. A genome-wide association study meta-analysis of menstrual cycle length in 44 871 women of European ancestry confirmed the previously observed association with the FSHB locus and identified four additional novel signals in, or near, the GNRH1, PGR, NR5A2 and INS-IGF2 genes. These findings not only confirm the role of the hypothalamic–pituitary–gonadal axis in the genetic regulation of menstrual cycle length but also highlight potential novel local regulatory mechanisms, such as those mediated by IGF2

Role of Inn1 and its interactions with Hof1 and Cyk3 in promoting cleavage furrow and septum formation in S. cerevisiae

Cytokinesis requires coordination of actomyosin ring (AMR) contraction with rearrangements of the plasma membrane and extracellular matrix. In Saccharomyces cerevisiae, new membrane, the chitin synthase Chs2 (which forms the primary septum [PS]), and the protein Inn1 are all delivered to the division site upon mitotic exit even when the AMR is absent. Inn1 is essential for PS formation but not for Chs2 localization. The Inn1 C-terminal region is necessary for localization, and distinct PXXP motifs in this region mediate functionally important interactions with SH3 domains in the cytokinesis proteins Hof1 (an F-BAR protein) and Cyk3 (whose overexpression can restore PS formation in inn1Δ cells). The Inn1 N terminus resembles C2 domains but does not appear to bind phospholipids; nonetheless, when overexpressed or fused to Hof1, it can provide Inn1 function even in the absence of the AMR. Thus, Inn1 and Cyk3 appear to cooperate in activating Chs2 for PS formation, which allows coordination of AMR contraction with ingression of the cleavage furrow

Brooke Family papers, Series 2, Box 1, Folder 37: Correspondence -- To Charles H. Brooke -- From Margaret Lippincott, [1860s]

Correspondence to Charles H. Brooke -- From Margaret Lippincott, [1860s]. Complete information may be found in the finding aid to the collection at: http://hdl.handle.net/1903.1/1740

Isolation and characterization of cytokinesis mutants in Saccharomyces cerevisiae

Cytokinesis in Saccharomyces cerevisiae can occur via the contraction of an actomyosin ring or through septum formation. Although the actomyosin contractile ring is not essential, S. cerevisiae strains deleted for hofl, a gene important for septum formation, are dependent on the actomyosin contractile ring for cytokinesis and viability (Vallen et al. 2000). A screen for mutants synthetically lethal with hofl was utilized to identify genes required for the function of the actomyosin pathway. Forty-one HOFl - dependent mutants were identified by screening 33,000 mutagenized colonies using a sectoring assay and other genetic tests.\ud Genetic analysis suggests that the 34 recessive mutants fall into 18 complementation groups, 11 of which are single alleles. Seven mutants have dominant mutations or exhibit unlinked non-complementation; it is not yet known how many loci this represents. Complementation testing and plasmid-linked suppression indicates that three of the complementation groups are MYOl, BNIl, and CYK3. Interestingly, some of the myol and cyk3 mutants appear to exhibit unlinked non-complementation. Phenotypic analysis including Hoechst staining of DNA, rhodamine-phalliodin staining of the actin cytoskeleton, DIC microscopic analysis, and zymolyase treatment was used to characterize mutants. Results indicate that four mutants that may affect the actin-myosin pathway and cytokinesis are worthy of further analysis

Isolation and characterization of cytokinesis mutants in Saccharomyces cerevisiae

Cytokinesis in Saccharomyces cerevisiae can occur via the contraction of an actomyosin ring or through septum formation. Although the actomyosin contractile ring is not essential, S. cerevisiae strains deleted for hof1, a gene important for septum formation, are dependent on the actomyosin contractile ring for cytokinesis and viability (Vallen et al. 2000). A screen for mutants synthetically lethal with hof1 was utilized to identify genes required for the function of the actomyosin pathway. Forty-one HOF1-dependent mutants were identified by screening 33,000 mutagenized colonies using a sectoring assay and other genetic tests. Genetic analysis suggests that the 34 recessive mutants fall into 18 complementation groups, 11 of which are single alleles. Seven mutants have dominant mutations or exhibit unlinked non-complementation; it is not yet known how many loci this represents. Complementation testing and plasmid-linked suppression indicates that three of the complementation groups are MYO1, BNI1, and CYK3. Interestingly, some of the myo1 and cyk3 mutants appear to exhibit unlinked non-complementation. Phenotypic analysis including Hoechst staining of DNA, rhodamine-phalliodin staining of the actin cytoskeleton, DIC microscopic analysis, and zymolyase treatment was used to characterize mutants. Results indicate that four mutants that may affect the actin-myosin pathway and cytokinesis are worthy of further analysis

Discordance in the dependence on Kisspeptin signaling in mini puberty vs adolescent puberty: human genetic evidence

Context: Hypothalamic kisspeptin signaling plays a critical role in the initiation and maintenance of reproductive function. Biallelic mutations in the coding sequence of KISS1R (GPR54) have been identified in patients with idiopathic hypogonadotropic hypogonadism, but it is unknown whether biallelic variants can also be associated with related reproductive disorders. Case Description: A missense homozygous variant (c.890> T p. R297L) in KISS1R was identified in a child who presented with microphallus and bilateral cryptorchidism. This variant has been reported to reduce, but not abolish, postreceptor signaling in vitro. Biochemical evaluation during the neonatal period revealed low testosterone levels. By 11 years and 8 months, the boy began demonstrating increases in testicular volume. By 17 years and 3 months, his testicular volume was 20 mL; his penile length was 7.3 cm; and he had adult levels of circulating gonadotropins and testosterone. Conclusion: This case report associates biallelic loss-of-function mutations in KISS1R with normal timing of adolescent puberty. Because these coding sequence variants occurred in a patient with microphallus and cryptorchidism, they demonstrate different levels of dependence of the hypothalamic-pituitary-gonadal cascade on kisspeptin signaling at distinct times in the reproductive life span. The suppression of the hypothalamic-pituitary-gonadal cascade during early life but not adolescence suggests that the mini puberty of infancy depends more on kisspeptin-induced, gonadotropin-releasing hormone-induced luteinizing hormone secretion than does adolescent puberty.Eunice K. Shriver National Institute for Child Health and Human Development R01 HD043341 P50 HD-28138 Doris Duke Clinical Scientist Development Award 2013110 Catalyst Medical Research Investigator Training Award from Harvard Catalyst Fulbright Visiting Scholarshi