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991.
992.
The study of limb development has provided insight into pattern formation during vertebrate embryogenesis. Genetic approaches offer powerful ways to identify the critical molecules and their pathways of action required to execute a complex morphogenetic program. We have applied genetic analysis to the process of limb development by studying two mouse mutants, limb deformity (Id) and Strong's luxoid (Ist). These mutations confer contrasting phenotypic alterations to the anteroposterior limb pattern. The six mutant Id alleles are fully recessive and result in oligosyndactyly of all four limbs. By contrast, the two mutant Ist alleles result in a mirror-image polydactylous limb phenotype inherited in a semidominant fashion. Morphological and molecular analysis of embryonic limbs has shown that the Id and Ist alleles affect the extent and distribution of two key signaling centers differentially: the apical ectodermal ridge and the zone of polarizing activity. Molecular characterization of the Id gene has defined a new family of evolutionarily conserved proteins termed the formins. The underlying molecular defect in the Ist mutation has not been identified; however, both loci are tightly linked on mouse chromosome 2, suggesting the possibility that they may be allelic. In this study, we have used genetic analysis to examine the epistatic and allelic relationships of Id and Ist. We observed that in + Id/Ist + double heterozygotes, a single mutant Id allele is able to suppress the semi-dominant polydactylous Ist limb phenotype. By segregating the Ist and Id loci in a backcross, we observed that these loci recombine and are separated by a genetic distance of approximately 6 cM. Therefore, while our observations demonstrate a genetic interaction between Id and Ist, it is probable that Id and Ist are not allelic. Instead, Ist and Id may be operating either in a linear or in a parallel (bypass) genetic pathway to affect the limb signaling centers. © 1996 Wiley-Liss, Inc. 相似文献
993.
994.
Triploidy is a viable condition in teleosts. However, in many salmonids, the triploid condition in the female results in sterility as gametogenesis appears to be disrupted. Although the underlying mechanisms regulating the gonadal development of teleosts have not been clearly elucidated, the reversal of phenotypic sex by the administration of the appropriate exogenous steroid during early development supports the argument that gonadal steroids play a pivotal role in sexual differentiation and subsequent gonad development in these fish. To determine whether the failure of normal ovarian development in triploid female rainbow trout (Oncorhynchus mykiss) is due to an absence or reduction of endogenous sex steroids, ovarian morphology was compared between diploid and triploid juvenile rainbow trout treated with exogenous estradiol-17β (E2). The ovaries of both untreated and E2 treated diploid fish, at 145 days post-fertilization, contained synchronously developing oocytes in the perinucleolar stage, whereas ovaries from untreated and estradiol-treated triploid fish of the same age were considerably smaller and devoid of developing oocytes. No differences in the ovaries of triploid untreated fish and triploid fish treated with E2 were observed. It is reported that exposure to exogenous E2 during the period of gonadal differentiation is not sufficient to induce oocyte development in triploid rainbow trout. © 1996 Wiley-Liss, Inc. 相似文献
995.
996.
Luciana Cordeiro Rosa Eliane Cristina Silva Dias Renatta Silva Melo Carla Janaína Rebouas Marques do Rosrio Felipe Lucas Correa Pereira Luiz Bruno Oliveira Chung Adriana Raquel de Almeida da Anunciao Felipe de Jesus Moraes Junior Fernando Andrade Souza Ricardo de Macêdo Chaves 《Animal Reproduction》2022,19(1)
This study aimed to evaluate the effect of synchronization with prostaglandin F2α in Baixadeiro mares during the rainy and dry seasons. Fourteen mares were synchronized by administering two doses of 1 mL prostaglandin PGF 2α and monitored by rectal palpation and ultrasound for the assessment of follicular development and uterine echotexture. Of this total, nine mares allowed the collection of blood, in which the blood was collected by venipuncture of the jugular vein to determine progesterone (P4) by ELISA. Mares showed no differences (P > 0.05) in weight, body score condition (BSC), tone, uterine edema, frequency of ovulation, synchronization interval, estrus, and the total number of follicles between periods. However, there was a difference in large increased follicle diameter (P < 0.05) during the dry season. The average concentrations of P4 in mares differed (P < 0.05) between the pre- and post-ovulatory phases for both seasons and after ovulation, with higher concentrations in the rainy season. Furthermore, statistical differences in daily light (P < 0.05) were observed between the dry and rainy periods. Thus, we conclude that mares from the genetic grouping Baixadeiro showed no reproductive seasonality, though there was a difference in luminosity between the rainy and dry seasons. The treatment with two doses of PGF 2α was effective in synchronizing the mares, promoting the return of estrus in the dry and rainy periods. The mares remaining cyclically active throughout the year provided there were appropriate forage availability and quality levels to allow for normal values of body weight and condition. 相似文献
997.
998.
Johannes Schilling Christian Jost Ioana Mariuca Ilie Joachim Schnabl Oralea Buechi Rohan S. Eapen Rafaela Truffer Amedeo Caflisch Patrik Forrer 《The Journal of biological chemistry》2022,298(1)
Designed ankyrin repeat proteins (DARPins) are antibody mimetics with high and mostly unexplored potential in drug development. By using in silico analysis and a rationally guided Ala scanning, we identified position 17 of the N-terminal capping repeat to play a key role in overall protein thermostability. The melting temperature of a DARPin domain with a single full-consensus internal repeat was increased by 8 °C to 10 °C when Asp17 was replaced by Leu, Val, Ile, Met, Ala, or Thr. We then transferred the Asp17Leu mutation to various backgrounds, including clinically validated DARPin domains, such as the vascular endothelial growth factor-binding domain of the DARPin abicipar pegol. In all cases, these proteins showed improvements in the thermostability on the order of 8 °C to 16 °C, suggesting the replacement of Asp17 could be generically applicable to this drug class. Molecular dynamics simulations showed that the Asp17Leu mutation reduces electrostatic repulsion and improves van-der-Waals packing, rendering the DARPin domain less flexible and more stable. Interestingly, this beneficial Asp17Leu mutation is present in the N-terminal caps of three of the five DARPin domains of ensovibep, a SARS-CoV-2 entry inhibitor currently in clinical development, indicating this mutation could be partly responsible for the very high melting temperature (>90 °C) of this promising anti-COVID-19 drug. Overall, such N-terminal capping repeats with increased thermostability seem to be beneficial for the development of innovative drugs based on DARPins. 相似文献
999.
Signaling by bone morphogenetic proteins (BMPs) plays pivotal roles in embryogenesis, adult tissue homeostasis, and disease. Recent studies revealed that the well-established WNT agonist R-spondin 2 (RSPO2) is also a BMP receptor (BMP receptor type 1A) antagonist, with roles in early Xenopus embryogenesis and human acute myeloid leukemia (AML). To uncouple the BMP antagonist function from the WNT agonist function and to promote development of AML therapeutics, here we identified a 10-mer peptide (RW) derived from the thrombospondin 1 domain of RSPO2, which specifically prevents binding between RSPO2 and BMP receptor type 1A without altering WNT signaling. We also show that a corresponding RW dendrimer (RWd) exhibiting improved half-life relieves inhibition of BMP receptor signaling by RSPO2 in human AML cells, reduces cell growth, and induces differentiation. Moreover, microinjection of RWd in Xenopus embryos ventralizes the dorsoventral embryonic patterning by upregulating BMP signaling without affecting WNT signaling. Our study corroborates the function of RSPO2 as a BMP receptor antagonist and provides a proof of concept for pharmacologically uncoupling BMP antagonist from WNT agonist functions of RSPO2 using the inhibitor peptide RWd with enhanced target selectivity and limited side effects. 相似文献
1000.
Beni Lestari Satomi Naito Akinori Endo Hidenori Nishihara Akira Kato Erika Watanabe Kimitoshi Denda Masayuki Komada Toshiaki Fukushima 《Molecular biology and evolution》2022,39(2)
The molecular evolution processes underlying the acquisition of the placenta in eutherian ancestors are not fully understood. Mouse NCK-interacting kinase (NIK)-related kinase (NRK) is expressed highly in the placenta and plays a role in preventing placental hyperplasia. Here, we show the molecular evolution of NRK, which confers its function for inhibiting placental cell proliferation. Comparative genome analysis identified NRK orthologs across vertebrates, which share the kinase and citron homology (CNH) domains. Evolutionary analysis revealed that NRK underwent extensive amino acid substitutions in the ancestor of placental mammals and has been since conserved. Biochemical analysis of mouse NRK revealed that the CNH domain binds to phospholipids, and a region in NRK binds to and inhibits casein kinase-2 (CK2), which we named the CK2-inhibitory region (CIR). Cell culture experiments suggest the following: 1) Mouse NRK is localized at the plasma membrane via the CNH domain, where the CIR inhibits CK2. 2) This mitigates CK2-dependent phosphorylation and inhibition of PTEN and 3) leads to the inhibition of AKT signaling and cell proliferation. Nrk deficiency increased phosphorylation levels of PTEN and AKT in mouse placenta, supporting our hypothesis. Unlike mouse NRK, chicken NRK did not bind to phospholipids and CK2, decrease phosphorylation of AKT, or inhibit cell proliferation. Both the CNH domain and CIR have evolved under purifying selection in placental mammals. Taken together, our study suggests that placental mammals acquired the phospholipid-binding CNH domain and CIR in NRK for regulating the CK2–PTEN–AKT pathway and placental cell proliferation. 相似文献