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PubMed1994

The Drosophila 18 wheeler is required for morphogenesis and has striking similarities to Toll.

We have isolated and characterized a novel gene, named 18 wheeler (18w) for its unique segmental expression pattern in Drosophila embryos and expression in cells that migrate extensively. 18 wheeler transcripts accumulate in embryos in a pattern reminiscent of segment polarity genes. Mutations in 18w cause death during larval development and early adulthood. Escaping mutant adults often display leg, antenna, and wing deformities, presumably resulting from improper eversion of imaginal discs. Sequence analysis indicates that 18w encodes a transmembrane protein with an extracellular moiety containing many leucine rich repeats and cysteine motifs, and an intracellular domain bearing homology to the cytoplasmic portion of the interleukin-1-receptor. Expression of 18W protein in non-adhesive Schneider 2 cells promotes rapid and robust aggregation of cells. Analysis of the expression of 18w in different mutant backgrounds shows that it is under control of segment polarity and homeotic genes. The data suggest that the 18W protein participates in the developmental program specified by segmentation and homeotic genes as a cell adhesion or receptor molecule that facilitates cell movements.

Amino Acid Sequence↗

PubMed1995

Modifications of cell fate specification in equal-cleaving nemertean embryos: alternate patterns of spiralian development.

The nemerteans belong to a phylum of coelomate worms that display a highly conserved pattern of cell divisions referred to as spiral cleavage. It has recently been shown that the fates of the four embryonic cell quadrants in two species of nemerteans are not homologous to those in other spiralian embryos, such as the annelids and molluscs (Henry, J. Q. and Martindale, M. Q. (1994a) Develop. Genetics 15, 64-78). Equal-cleaving molluscs utilize inductive interactions to establish quadrant-specific cell fates and embryonic symmetry properties following fifth cleavage. In order to elucidate the manner in which cell fates are established in nemertean embryos, we have conducted cell isolation and deletion experiments to examine the developmental potential of the early cleavage blastomeres of two equal-cleaving nemerteans, Nemertopsis bivittata and Cerebratulus lacteus. These two species display different modes of development: N. bivittata develops directly via a non-feeding larvae, while C. lacteus develops to form a feeding pilidium larva which undergoes a radical metamorphosis to give rise to the juvenile worm. By examining the development of certain structures and cell types characteristic of quadrant-specific fates for each of these species, we have shown that isolated blastomeres of the indirect-developing nemertean, C. lacteus, are capable of generating cell fates that are not a consequence of that cell's normal developmental program. For instance, dorsal blastomeres can form muscle fibers when cultured in isolation. In contrast, isolated blastomeres of the direct-developing species, N. bivittata do not regulate their development to the same extent. Some cell fates are specified in a precocious manner in this species, such as those that give rise to the eyes. Thus, these findings indicate that equal-cleaving spiralian embryos can utilize different mechanisms of cell fate and axis specification. The implications of these patterns of nemertean development are discussed in relation to experimental work in other spiralian embryos, and a model is presented that accounts for possible evolutionary changes in cell lineage and the process of cell fate specification amongst these protostome phyla.

Animals↗

PubMed1995

Fusion from myoblasts to myotubes is dependent on the rolling stone gene (rost) of Drosophila.

The development and differentiation of the body wall musculature in Drosophila are accompanied by changes in gene expression and cellular architecture. We isolated a Drosophila gene, termed rolling stone (rost), which, when mutated, specifically blocks the fusion of mononucleated cells to myotubes in the body wall musculature. beta 3 tubulin, which is an early marker for the onset of mesoderm differentiation, is still expressed in these cells. Gastrulation and mesoderm formation, as well as the development of the epidermis and of the central and peripheral nervous systems, appear quite normal in homozygous rolling stone embryos. Embryonic development stops shortly before hatching in a P-element-induced mutant, as well as in 16 EMS-induced alleles. In mutant embryos, other mesodermal derivatives such as the visceral mesoderm and the dorsal vessel, develop fairly normally and defects are restricted to the body wall musculature. Myoblasts remain as single mononucleated cells, which express muscle myosin, showing that the developmental program of gene expression proceeds. These myoblasts occur at positions corresponding to the locations of dorsal, ventral and pleural muscles, showing that the gene rolling stone is involved in cell fusion, a process that is independent of cell migration in these mutants. This genetic analysis has set the stage for a molecular analysis to clarify where the rolling stone action is manifested in the fusion process and thus gives insight into the complex regulating network controlling the differentiation of the body wall musculature.

Animals↗

PubMed2000

Regulation of cell proliferation and patterning in Drosophila oogenesis by Hedgehog signaling.

The localized expression of Hedgehog (Hh) at the extreme anterior of Drosophila ovarioles suggests that it might provide an asymmetric cue that patterns developing egg chambers along the anteroposterior axis. Ectopic or excessive Hh signaling disrupts egg chamber patterning dramatically through primary effects at two developmental stages. First, excess Hh signaling in somatic stem cells stimulates somatic cell over-proliferation. This likely disrupts the earliest interactions between somatic and germline cells and may account for the frequent mis-positioning of oocytes within egg chambers. Second, the initiation of the developmental programs of follicle cell lineages appears to be delayed by ectopic Hh signaling. This may account for the formation of ectopic polar cells, the extended proliferation of follicle cells and the defective differentiation of posterior follicle cells, which, in turn, disrupts polarity within the oocyte. Somatic cells in the ovary cannot proliferate normally in the absence of Hh or Smoothened activity. Loss of protein kinase A activity restores the proliferation of somatic cells in the absence of Hh activity and allows the formation of normally patterned ovarioles. Hence, localized Hh is not essential to direct egg chamber patterning.

Animals↗

PubMed2000

Transdifferentiation of esophageal smooth to skeletal muscle is myogenic bHLH factor-dependent.

Previously, coexpression of smooth and skeletal differentiation markers, but not myogenic regulatory factors (MRFs), was observed from E16.5 mouse fetuses in a small percentage of diaphragm level esophageal muscle cells, suggesting that MRFs are not involved in the process of initiation of developmentally programmed transdifferentiation in the esophagus. To investigate smooth-to-skeletal esophageal muscle transition, we analyzed Myf5nlacZ knock-in mice, MyoD-lacZ and myogenin-lacZ transgenic embryos with a panel of the antibodies reactive with myogenic regulatory factors (MRFs) and smooth and skeletal muscle markers. We observed that lacZ-expressing myogenic precursors were not detected in the esophagus before E15.5, arguing against the hypothesis that muscle precursor cells populate the esophagus at an earlier stage of development. Rather, the expression of the MRFs initiated in smooth muscle cells in the upper esophagus of E15.5 mouse embryos and was immediately followed by the expression of skeletal muscle markers. Moreover, transdifferentiation was markedly delayed or absent only in the absence of Myf5, suggesting that appropriate initiation and progression of smooth-to-skeletal muscle transdifferentiation is Myf5-dependent. Accordingly, the esophagus of Myf5(-/-):MyoD(-/-)embryos completely failed to undergo skeletal myogenesis and consisted entirely of smooth muscle. Lastly, extensive proliferation of muscularis precursor cells, without programmed cell death, occurred concomitantly with esophageal smooth-to-skeletal muscle transdifferentiation. Taken together, these results indicate that transdifferentiation is the fate of all smooth muscle cells in the upper esophagus and is normally initiated by Myf5.

Animals↗

PubMed2002

Mosaic analyses reveal the function of Drosophila Ras in embryonic dorsoventral patterning and dorsal follicle cell morphogenesis.

In Drosophila melanogaster, the Ras signal transduction pathway is the primary effector of receptor tyrosine kinases, which govern diverse developmental programs. During oogenesis, epidermal growth factor receptor signaling through the Ras pathway patterns the somatic follicular epithelium, establishing the dorsoventral asymmetry of eggshell and embryo. Analysis of follicle cell clones homozygous for a null allele of Ras demonstrates that Ras is required cell-autonomously to repress pipe transcription, the critical first step in embryonic dorsoventral patterning. The effects of aberrant pipe expression in Ras mosaic egg chambers can be ameliorated, however, by post-pipe patterning events, which salvage normal dorsoventral polarity in most embryos derived from egg chambers with dorsal Ras clones. The patterned follicular epithelium also determines the final shape of the eggshell, including the dorsal respiratory appendages, which are formed by the migration of two dorsolateral follicle cell populations. Confocal analyses of mosaic egg chambers demonstrate that Ras is required both cell- and non cell-autonomously for morphogenetic behaviors characteristic of dorsal follicle cell migration, and reveal a novel, Ras-dependent pattern of basal E-cadherin localization in dorsal midline follicle cells.

Animals↗

PubMed2003

Inhibitory neurons from fetal rat cerebral cortex exert delayed axon formation and active migration in vitro.

Inhibitory and excitatory neurons exhibit distinct patterns of development in the mammalian cerebral cortex. The morphological development of inhibitory and excitatory neurons derived from fetal rat cerebral cortex has now been compared in vitro. Inhibitory neurons were identified by immunofluorescence staining with antibodies to gamma-aminobutyric acid, and axon formation was detected by staining with antibodies to phosphorylated neurofilaments. In chemically defined, glia-free and low-density cultures, excitatory neurons formed axons within three days of plating. By contrast, inhibitory neurons required more than six days to form axons. Time-lapse analysis over six days revealed that most inhibitory neurons were bipolar and that their two processes exhibited alternate growth and retraction without giving rise to axons. Movement of the cell body towards the growing process was apparent in about one-half of inhibitory neurons, whereas such movement was never seen in excitatory neurons. The migratory behavior of neurons was further investigated by culture on a glial cell monolayer. Inhibitory neurons migrated over substantially larger distances than did excitatory neurons. The centrosome of inhibitory neurons translocated to the base of the newly emerging leading process, suggesting the existence of a force that pulls intracellular organelles towards the leading process. Centrosome translocation was not detected in excitatory neurons. These observations suggest that the developmental programs of excitatory and inhibitory neurons differ. Inhibitory neurons thus possess a more effective cytoskeletal machinery for migration than excitatory neurons and they form axons later.

Animals↗

PubMed2004

Translocation of the Dictyostelium TRAP1 homologue to mitochondria induces a novel prestarvation response.

Dd-TRAP1 is a Dictyostelium homologue of tumor necrosis factor receptor-associated protein 1 (TRAP-1). Dd-TRAP1 is located in the cortex of cells growing at a low density, but was found to be translocated to mitochondria with the help of a novel prestarvation factor that was accumulated in growth medium along with increased cell densities. The knockdown mutant of Dd-TRAP1 (TRAP1-RNAi cells) exhibited a significant defect in prestarvation response. Although TRAP1-RNAi cells showed normal expressions of classical prestarvation genes [dscA (discoidin I) and car1 (carA; cAMP receptor)], the expression of differentiation-associated genes (dia1 and dia3) induced by the prestarvation response were markedly repressed. By contrast, transformants overexpressing Dd-TRAP1 showed an early prestarvation response and also increased expression of dia1 and dia3 in a cell-density-dependent manner. Importantly, introduction of Dd-TRAP1 antibody into D. discoideum Ax-2 cells by electroporation inhibited the translocation of Dd-TRAP1 from the cortex to mitochondria and greatly inhibited the initiation of differentiation. Taken together, these results indicate that Dd-TRAP1 is translocated to mitochondria by sensing the cell density in growth medium and enhances the early developmental program through a novel prestarvation response.

Animals↗

PubMed1996

The fission yeast sts5+ gene is required for maintenance of growth polarity and functionally interacts with protein kinase C and an osmosensing MAP-kinase pathway.

Cell morphogenesis is a fundamental phenomenon that involves understanding a number of biological processes including the developmental program, polarity and cell division. Fission yeast sts5 mutant cells are round rather than cylindrical with cortical actin randomly dispersed. Genetic analyses demonstrate that the sts5+ gene is required for maintenance of cell shape during interphase when the cell normally exhibits polarised growth. The sts5 mutant is not defective in cell wall integrity. Deletion of ppe1+, which encodes a type 2A-like protein phosphatase, shows similar phenotypes to the sts5 mutant and these two mutations are synthetically lethal. Multicopy plasmids containing either the protein kinase C-like gene pck1+ or the protein tyrosine phosphatase pyp1+, an inhibitor of an osmosensing Sty1/Spc1 MAP-kinase, are capable of suppressing the sts5 mutation. Consistent with this, we have found that the wis1 mutation, which is defective in a MAP-kinase kinase of the pathway, suppresses the sts5 mutation. The predicted sts5+ gene product exhibits sequence similarity to two yeast proteins, Dis3 and Ssd1 and a nematode protein, F46E8.6, where the former two yeast proteins have been shown to be involved in cell cycle control and cell morphogenesis. The sts5+ gene is not essential for cell viability, but is absolutely required for polarised growth as the gene disruption showed the same phenotypes as those of the original mutants. Overexpression of the sts5+ gene resulted in altered cell morphology and, cortical actin in these overproducing cells was also abnormal, fainter and often dispersed. Anti-Sts5 antibody specifically detected a 130 kDa protein by western blotting. A green fluorescent protein-Sts5 fusion protein localised in the cytoplasm with a discrete punctate pattern, suggesting that the Sts5 protein is a component of a novel structure. These results have indicated that the Sts5 protein is a crucial determinant of polarised growth and that it functionally interacts with the serine/threonine phosphatase, protein kinase C, and an osmosensing MAP-kinase to maintain cell morphology.

Amino Acid Sequence↗

PubMed1999

The four populations of myoblasts involved in human limb muscle formation are present from the onset of primary myotube formation.

To understand how and when myogenic precursor cells become committed to their particular developmental programs, we have analysed the different populations of myoblasts which grow out from explants of muscle tissue isolated from human limb buds from the beginning of primary fibre formation throughout subsequent development and post-natal growth. Four phenotypically distinct types of myoblasts were identified on the basis of their expression of desmin, myogenin and myosin heavy chain isoforms (MyHC), and after 5 and 20 divisions, cells were cloned. All four types of myoblasts were present at the beginning of primary myogenesis. Each respective phenotype was stably heritable through cloning and subsequent proliferation. The type 1 clones correspond to a novel class of myoblasts never described during human development, that biochemically differentiates, but does not fuse. Type 2 clones are composed of small myotubes expressing only embryonic MyHC. Type 3 clones are composed of thin and long myotubes expressing both embryonic and fetal MyHCs. The type 4 clones are composed of myotubes that have a phenotype very similar to human satellite cells. Contrasting with others species, no other population of myoblasts appear during fetal development and only the relative number of these four types changes.

Cell Differentiation↗

PubMed2001

Fission yeast mfr1 activates APC and coordinates meiotic nuclear division with sporulation.

Meiosis is the developmental program by which sexually reproducing diploid organisms generate haploid gametes. In yeast, meiosis is followed by spore morphogenesis. These two events are normally coordinated in such a way that spore formation is dependent upon completion of the meiotic nuclear divisions. Here we describe a meiosis-specific protein, mfr1, that is involved in this coordination. mfr1 is an activator of the anaphase-promoting complex (APC), which is necessary for the rapid degradation of the cdc13 cyclin at the end of meiosis II, prior to the formation of spores. An mfr1 null mutant completes meiosis II but remains with high levels of cdc13 and cdc2 kinase activity and has considerably delayed spore formation. By analogy with the mitotic cell cycle, where proteolysis and inactivation of cdc2 kinase are necessary to trigger mitotic exit and cytokinesis, we propose that at the end of meiosis rapid and timely proteolysis of cyclins is required to switch on the differentiation program that eventually leads to the formation of haploid gametes.

Amino Acid Sequence↗

PubMed2002

Mechanisms for targeting of the Saccharomyces cerevisiae GPI-anchored cell wall protein Crh2p to polarised growth sites.

The cell wall is an essential structure that preserves the osmotic integrity of fungal cells and determines cellular morphology during developmental programs. The high number of different wall components demands a variety of processes to deliver precursors and synthetic proteins to the proper location at the right time for wall development and modification. Here, the specificity of the mechanisms that regulate the temporal and spatial localisation of cell wall proteins to sites of polarised growth in Saccharomyces cerevisiae is investigated. For this purpose, the localisation of Crh2p, a cell wall glycosylphosphatidylinositol (GPI)-anchored mannoprotein that we have recently described as involved in cell wall construction and localised to polarised growth sites, was followed using a Crh2p-GFP fusion protein. Crh2p distribution was studied in several genetic backgrounds affected in different steps of the cell polarity establishment machinery or/and bud morphogenesis. Crh2p is localised at the mother-bud neck in bud1 cells following the random budding pattern characteristic of this mutant. The Crh2p distribution was greatly altered in a cdc42-1 mutant, indicating complete dependence on an organised actin cytoskeleton for polarised Crh2p distribution. The usual deposition of Crh2p in a ring at the base of growing buds was lacking in cdc10-11 cells growing under restrictive temperature conditions, whereas Crh2p deposition at the septum region was absent in both cdc10-11 and cdc15-lyt1 cells. These results point to the dependence of Crh2p localisation at the bud-neck on both septins and septum integrity. Furthermore, in the absence of Bni4p, a scaffold protein involved in the targeting of the chitin synthase III complex to the bud neck, Crh2p was not longer found at the neck in large-budded cells undergoing cytokinesis. Finally, Crh2p was not properly localised in cells deleted in CHS5, which encodes a protein involved in the transport of Chs3p, and was completely mislocalised in sbe2/sbe22 mutants, suggesting that the transport systems for Chs3p and Crh2p are to a certain extent coincident. The transport of other GPI-cell wall proteins, such as Cwp1p, however, does not depend on these systems as the localisation of the latter protein was not affected in either of these mutants.

Actin Cytoskeleton↗

PubMed1990

Growth and differentiation factors of pluripotential stem cells.

The mammalian embryo develops as a quasi-stem cell system whose differentiation and pluripotentiality in vitro is controlled by a single regulatory factor, Differentiation Inhibiting Activity/Leukemia Inhibitory Factor (DIA/LIF). DIA/LIF is expressed in two distinct functional forms, derived from the use of alternate transcriptional start sites, one of which is freely diffusible and the other tightly associated with the extracellular matrix. The dissemination of the DIA/LIF signal is therefore under specific molecular control. The expression of DIA/LIF in vitro is both developmentally programmed and controlled by the action of other growth factors, the most notable of which are members of the fibroblast growth factor family expressed by the stem cells themselves. This indicates that differentiation and proliferation in early development of the mouse are controlled, at least in part, by an interactive network of specific growth and differentiation regulatory factors.

Amino Acid Sequence↗

PubMed1987

Cytoplasmic pH at the onset of development in Dictyostelium.

Cytoplasmic pH (pHi) was measured by a pH 'null point' method in synchronous populations of Dictyostelium discoideum cells. Synchronous populations of vegetative cells with a lower pHi than asynchronous populations of vegetative cells show a clear preference for the prespore differentiation pathway when they enter development. Treatment of these cells before development with the weak base ammonia results in an increase in pHi and an abolition of the preference of the cells for the prespore pathway. On the other hand, synchronous populations of vegetative cells with the same pHi as asynchronous populations of vegetative cells resemble these last cells in that they show no preference for a certain differentiation direction when they enter development. However, both these synchronous and asynchronous populations of cells do acquire a preference for the prespore pathway when they are treated before development with the weak acid 5,5-dimethyl-2,4-oxazolidineolione (DMO), which lowers their pHi. It is concluded that changes in pHi at the onset of the developmental program lead to significant changes in the preference of the cells for the prespore differentiation pathway in Dictyostelium discoideum.

Cell Count↗

PubMed1990

Cells of the cellular immune and hemopoietic system of the mouse lack lamins A/C: distinction versus other somatic cells.

Almost all somatic cells in adult murine tissues express all three nuclear lamins (A, B, C). Here we demonstrate that cells of the hemopoietic system of the adult mouse are an exception in that they express only lamin B. Thus T and B lymphocytes as well as granulocytes and monocytic cells directly isolated from spleen, thymus, blood or bone marrow do not express lamin A/C but only lamin B. In agreement with this observation the murine hemopoietic cell lines EL4, BW5147, HK22, 70Z/3, SP2/0 and PAI express only lamin B. In immunoblotting experiments used to confirm the immunofluorescence data no lamin A/C expression was detected. However, we noticed that murine lamin B occurs in two isoforms, which can be distinguished immunologically. These results reinforce the idea that a functional nuclear lamina can be formed from lamin B alone. They also pose the question of whether cells lacking lamin A/C are more plastic in their developmental programs than those that express all three lamins.

Animals↗

PubMed2001

Effects of the sap of the common oleander Nerium indicum (Apocyanaceae) on male fertility and spermatogenesis in the oriental tobacco budworm Helicoverpa assulta (Lepidoptera, Noctuidae).

We investigated the effects of sap of the common oleander Nerium indicum (Apocyanaceae) on male fertility and spermatogenesis in the oriental tobacco budworm Helicoverpa assulta. We found that continuous feeding of oleander sap during the larval period significantly affects fertility in males but not in females. This effect was also induced by direct injection of oleander sap into the hemocoel of 2-day-old pupae. Histological analyses of developing testes following oleander injection revealed a developmental delay and progressively more severe morphological abnormalities in the later stages of development. The effects of oleander sap on spermatogenesis in H. assulta were associated with greatly reduced levels of the two major polyamines, spermidine and spermine, in testis compared with saline-injected controls. In contrast, levels of putrescine, which is a precursor of both spermidine and spermine, and the activities of the enzymes ornithine decarboxylase and arginine decarboxylase, which are involved in the biosynthesis of putrescine, were initially elevated following oleander injection, but subsequently failed to undergo the induction that normally occurs during late pupal development. The effects of oleander sap on spermidine and spermine levels could be the result of direct inhibition by chemical constituents of the oleander sap of one of the enzymes used in common in the conversions of putrescine to spermidine and spermidine to spermine; alternatively, these effects on polyamine metabolism could be secondary to the disruption of a more fundamental process in the developmental program guiding spermatogenesis in H. assulta.

Animals↗

PubMed2002

Hatching controlled by the circatidal clock, and the role of the medulla terminalis in the optic peduncle of the eyestalk, in an estuarine crab Sesarma haematocheir.

Embryos attached to the female crab Sesarma haematocheir hatch synchronously within 1 h. Hatching is also synchronized near the time of the expected nocturnal high tide. These events are governed by a single circatidal clock (or pacemaker) in the female crab. The present study examined the role of the optic peduncle of the eyestalk on hatching and hatching synchrony. Surgery was performed either from the tip of the eyestalk [to remove the region of the optic peduncle from the compound eye-retina complex to the medulla interna (MI)] or from a small triangle 'window' opened on the eyestalk exoskeleton [to create lesions on the medulla terminalis (MT) of the optic peduncle]. Neither hatching nor hatching synchrony was affected by removal of the region of the optic peduncle from the compound eye-retina complex to the MI: the circatidal rhythm also remained. Removal of the MI probably caused damage to the sinus gland and the bundle of axons running from the sinus gland to the X organ. Nevertheless, maintenance of highly synchronized hatching indicates that the X organ-sinus gland system is not related to hatching. Hatching and hatching synchrony were not affected by dorsal-half cuts of the MT: the timing of hatching was not affected either. By contrast, transverse and ventral-half cuts of the MT caused severe damage to most females; hatching of many females was suppressed, while hatching of some females was either periodic, at intervals of approximately 24 h, or arrhythmic for a few days. The bundle of neuronal axons is tangled in the MT, and the axons inducing hatching pass through the ventral half of the MT. Complete incision of these axon bundles may have suppressed hatching. Incomplete incision of the axon bundle or partial damage to the neurons may have caused periodic or arrhythmic patterns of hatching. There are two possible roles for MT in hatching. One possibility is that neurons in the MT only induce hatching under the control of the circatidal pacemaker located in a site somewhere other than the optic peduncle. Another possibility is that the circatidal pacemaker is actually present in the MT. The second possibility seems more plausible. Each embryo has a special 48-49.5 h developmental program for hatching. This program could be initiated by the circatidal pacemaker in the female, and hatching synchrony may also be enhanced by the same pacemaker.

Animals↗

PubMed2005

Basal immunoglobulin signaling actively maintains developmental stage in immature B cells.

In developing B lymphocytes, a successful V(D)J heavy chain (HC) immunoglobulin (Ig) rearrangement establishes HC allelic exclusion and signals pro-B cells to advance in development to the pre-B stage. A subsequent functional light chain (LC) rearrangement then results in the surface expression of IgM at the immature B cell stage. Here we show that interruption of basal IgM signaling in immature B cells, either by the inducible deletion of surface Ig via Cre-mediated excision or by incubating cells with the tyrosine kinase inhibitor herbimycin A or the phosphatidylinositol 3-kinase inhibitor wortmannin, led to a striking "back-differentiation" of cells to an earlier stage in B cell development, characterized by the expression of pro-B cell genes. Cells undergoing this reversal in development also showed evidence of new LC gene rearrangements, suggesting an important role for basal Ig signaling in the maintenance of LC allelic exclusion. These studies identify a previously unappreciated level of plasticity in the B cell developmental program, and have important implications for our understanding of central tolerance mechanisms.

Androstadienes↗