Microbial pathogens must compete with the iron-withholding defense systems of their host to acquire this essential nutrient. Here, two high-affinity iron permease genes, CaFTR1 and CaFTR2, were isolated. CaFTR1 expression was induced under iron-limited conditions and repressed when iron supply was sufficient, whereas the expression of CaFTR2 was regulated in a reversed manner. Mutants lacking CaFTR1 but not CaFTR2 exhibited a severe growth defect in iron-deficient medium and were unable to establish systemic infection in mice. Thus, CaFTR1-mediated iron-uptake mechanism constitutes a virulence factor of Candida albicans and may be a target for the development of anti-Candida therapies.
Trk tyrosine kinases are receptors for members of the neurotrophin family and are crucial for growth and survival of specific populations of neurons. Yet, the functions of neurotrophin-Trk signaling in postnatal development as well as maintenance and plasticity of the adult nervous system are less clear. We report here the generation of mice harboring Trk knockin alleles that allow for pharmacological control of Trk kinase activity. Nanomolar concentrations of either 1NMPP1 or 1NaPP1, derivatives of the general kinase inhibitor PP1, inhibit NGF and BDNF signaling in TrkA(F592A) and TrkB(F616A) neurons, respectively, while no such Trk inhibition is observed in wild-type neurons. Moreover, oral administration of 1NMPP1 leads to specific inhibition of TrkA(F592A), TrkB(F616A), and TrkC(F167A) signaling in vivo. Thus, Trk knockin mice provide valuable tools for selective, rapid, and reversible inhibition of neurotrophin signaling in vitro and in vivo.
Sleep is important for memory consolidation and is responsive to waking experience. Clock circuitry is uniquely positioned to coordinate interactions between processes underlying memory and sleep need. Flies increase sleep both after exposure to an enriched social environment and after protocols that induce long-term memory. We found that flies mutant for rutabaga, period, and blistered were deficient for experience-dependent increases in sleep. Rescue of each of these genes within the ventral lateral neurons (LN V s) restores increased sleep after social enrichment. Social experiences that induce increased sleep were associated with an increase in the number of synaptic terminals in the LN V projections into the medulla. The number of synaptic terminals was reduced during sleep and this decline was prevented by sleep deprivation.Although sleep is a process that is necessary for survival, the functions of sleep are unknown (1,2). Sleep is regulated by circadian influences and is important for consolidation of longterm memory (LTM) (3-5). Additionally, LTM is modulated by circadian mechanisms (6,7). Because the relationship between sleep, memory, and circadian rhythms seem to be phylogenetically conserved, Drosophila can be used to explain mechanisms that coordinate these processes. Drosophila show an increase in daytime sleep after exposure to socially enriched environments (5). Similarly, an increase in sleep after courtship conditioning is necessary for LTM (5).Increased sleep after social enrichment is dependent upon genes that are required for learning and memory, including genes that alter cyclic adenosine monophosphate signaling (5). Although newly eclosed flies that are mutant for the adenylyl cyclase rutabaga (rut 2080 ) show increased sleep after social enrichment, 3-4-day-old adult rut mutants do not respond to changes in the social environment ( fig. S1). Elevating wild-type rut in adult flies with an RU486-inducible driver rescued experience-dependent increases in sleep in adult rut mutants (fig. S1); vehicle-treated siblings showed no increase in sleep ( fig. S1). To identify circuits that mediate experience-dependent increases in sleep, we used a series of GAL4 lines to drive wild-type rut expression in brain circuits (Fig. 1A). Figure S2 illustrates the data analysis used to quantify each GAL4 rescue. Expression of UAS-rut using pdf-GAL4 restored the increase in daytime sleep and daytime sleep-bout duration, although to a lesser extent than GSelav (Fig. 1, B to E). The expression pattern of pdf-GAL4 is limited to the ventral lateral neurons (LN V s), a group of clock neurons that express pigment-dispersing factor (pdf) (8,9). Although pdf is the only known output from the LN V s, flies mutant for pdf show a wild-type increase in sleep ( fig. S3).* To whom correspondence should be addressed. shawp@pcg.wustl.edu. (Fig. 1, I and J). per 01 ;per+7.2-2 flies displayed LTM (Fig. 1K) and increases in sleep (Fig. 1, L and M). Although per levels are low in mutants for Clock and cycle, both acquir...
Serum response factor (SRF) directs programs of gene expression linked to growth and muscle differentiation. To investigate the role of SRF in cardiovascular development, we generated mice in which SRF is knocked out in >80% of cardiomyocytes and >50% of vascular smooth muscle cells (SMC) through SM22␣-Cre-mediated excision of SRF's promoter and first exon. Mutant mice display vascular patterning, cardiac looping, and SRF-dependent gene expression through embryonic day (e)9.5. At e10.5, attenuation in cardiac trabeculation and compact layer expansion is noted, with an attendant decrease in vascular SMC recruitment to the dorsal aorta. Ultrastructurally, cardiac sarcomeres and Z disks are highly disorganized in mutant embryos. Moreover, SRF mutant mice exhibit vascular SMC lacking organizing actin͞intermediate filament bundles. These structural defects in the heart and vasculature coincide with decreases in SRF-dependent gene expression, such that by e11.5, when mutant embryos succumb to death, no SRFdependent mRNA expression is evident. These results suggest a vital role for SRF in contractile͞cytoskeletal architecture necessary for the proper assembly and function of cardiomyocytes and vascular SMC.Cre recombinase ͉ knockout ͉ myocardin ͉ SM22␣
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