Baker JC et al. (1997) Curr Opin Genet Dev "From receptor to nucleus: the Smad pathway."

Baker JC, Harland RM

[Curr Opin Genet Dev, 1997]

The transforming growth factor-beta (TGF-beta) superfamily plays a central role in the specification and patterning of cells in the early embryo. Several years ago, the TGF-betas were shown to signal through serine/threonine receptor kinases. Now, with the identification of Smad proteins, we can trace the TGF-beta signal transduction pathway from the receptors into the nucleus.

Hodgkin J (2002) Genes Dev "The remarkable ubiquity of DM domain factors as regulators of sexual phenotype: ancestry or aptitude?"

Hodgkin J

[Genes Dev, 2002]

The CM domain is a cysteine-rich DNA-binding motif first recognized in proteins encoded by the Drosophila set determination gene doublesex (Erdman and Burtis 1993; Zhu et al. 2000). As the name doublesex (dsx) suggests, this gene has functions in both sexes: Its transcripts undergo sex-specific alternative splicing, so that it can encode either a male-specific isoform, DSX(M), or a female-specific isoform, DSX(F) (Baker and Wolfner 1988; Burtis and Baker 1989). These proteins have the same N-terminal DNA-binding domain, but different C termini that confer different regulatory properties on the two forms. The expression of DSX(M) directs male development, and the expression of DSX(F) directs female development, throughout most of the somatic tissues of the fruit fly.

Culotti JG et al. (1977) Worm Breeder's Gazette "osmotic avoidance defective mutants of C elegans."

Culotti JG, Russell RL

[Worm Breeder's Gazette, 1977]

Seven independently derived mutants of C. elegans have been isolated for their inability to avoid high concentrations of NaCl or fructose at neutral pH. Behavioral characterization of double- backcrossed versions of these mutants reveals that (1) mutants isolated for their inability to avoid fructose are also unable to avoid NaCl and vice versa (the mutants are therefore believed defective in a single response to conditions of high molarity and hence are called 0smotic mutants), (2) all of the mutants are partially chemotaxis defective, and (3) all of the mutants are able to follow isothermal lines in a thermal gradient. With one exception, all of the chemotaxis and thermotaxis mutants previously isolated in this laboratory avoid high concentrations of NaCl essentially as does wild type. The exception is chemotaxis mutants of the complementation group tax-1 which avoid high concentrations of NaCl less well than wild type. These mutants represent a new complementation group required for the osmotic response. Genetic studies indicate that each of the mutant strains carries a single recessive mutation responsible for the osmotic phenotype. Three of the mutants are x-linked and four are autosomal. Only two of the mutants (JC-8 and JC-16, both X linked) are in the same complementation group. All seven of the mutants have been mapped to regions on four of the six C. elegans linkage groups. The JC-8, JC- 16 complementation group has been precisely mapped to the right end of the X chromosome 6.4 map units to the right of unc-3.Preliminary serial section EM results obtained by Dr. R. Ware (personal communication) suggest that a limited number of neurons in the anterior sensory nervous system are affected in mutant JC-11. The ciliated sensory endings of the 'lateral submedial' sensory neurons ( 'cephalics') are completely disorganized in this mutant even though their structurally similar neighbors the 'medial submedial' neurons ( 'outer labials') are not at all affected in this respect. The lateral submedial sensory neurons have been shown to contain dopamine (Sulston et. al., 1975). A quantitative radioenzymatic assay for catecholamines is now being used to determine dopamine levels in the osmotic avoidance defective mutants.

Boule JB et al. (2005) Nature "The yeast Pif1p helicase removes telomerase from telomeric DNA."

Boule JB, Zakian VA, Vega LR

[Nature, 2005]

Telomeres are the physical ends of eukaryotic chromosomes. Genetic studies have established that the baker''s yeast Pif1p DNA helicase is a negative regulator of telomerase, the specialized reverse transcriptase that maintains telomeric DNA, but the biochemical basis for this inhibition was unknown. Here we show that in vitro, Pif1p reduces the processivity of telomerase and releases telomerase from telomeric oligonucleotides. The released telomerase is enzymatically active because it is able to lengthen a challenger oligonucleotide. In vivo, overexpression of Pif1p reduces telomerase association with telomeres, whereas depleting cells of Pif1p increases the levels of telomere-bound Est1p, a telomerase subunit that is present on the telomere when telomerase is active. We propose that Pif1p helicase activity limits telomerase action both in vivo and in vitro by displacing active telomerase from DNA ends.

Gaffney, C. J. et al. (2013) International Worm Meeting "UNC-105 activation causes mitochondrial dysfunction and CED-4 dependent caspase-mediated protein degradation in terminally differentiated C. elegans muscle."

Rose, A., Chu, J., Greenhaff, P. L., Gaffney, C. J., Shephard, F., Constantin-Teodosiu, D., Baillie, D. L., Szewczyk, N. J.

[International Worm Meeting, 2013]

UNC-105 is an ENaC/Degenerin family ion channel. A dominant gain-of-function mutation in unc-105 was recently reported to cause aberrant muscle protein degradation. We found this degradation and the movement defect reduced in unc-105 mutants also containing either an intragenic premature stop codon or a mutation in let-2, which encodes a collagen that appears to gate the hyperactive UNC-105 channel. The degradation was not suppressed by mutations or drugs known to suppress proteasome-, autophagy-, or calpain-mediated degradation or by mutations known to suppress neurodegeneration in response to hyperactivation of other degenerin channels in C. elegans. However, protein degradation, but not the movement defect, was decreased by treatment with caspase inhibitors or RNAi against ced-3 or ced-4. To test if ion influx affected mitochondria, thereby triggering CED-4 release and CED-3 (caspase) activation, we examined mitochondria in wt, unc-105, and unc-105; let-2 animals. Adult unc-105 animals displayed a time dependent fragmentation of the mitochondrial network which was associated with impaired mitochondrial membrane potential both in vivo, as assessed by time dependent loss of JC-10 from muscle mitochondria, and in vitro, as assessed by decreased JC-1 uptake by isolated mitochondria. This loss of membrane potential correlated with decreased rates of maximal ATP production in mitochondria isolated from unc-105 mutants. Lastly, reduced levels of CED-4 were observed in mitochondrial isolations from unc-105 mutants and, interestingly, mitochondrial cytochrome C levels were also reduced. Thus, just as in mammalian cells, constitutive cationic influx into C. elegans muscle leads to pathological changes in mitochondrial architecture and function, release of mitochondrial proteins to the cytoplasm, and subsequent caspase activation.

Jantsch V et al. (2004) Mol Cell Biol "Targeted gene knockout reveals a role in meiotic recombination for ZHP-3, a Zip3-related protein in Caenorhabditis elegans."

Schweizer D, Mueller MM, Pasierbek P, Jantsch M, Loidl J, Jantsch V

[Mol Cell Biol, 2004]

The meiotically expressed Zip3 protein is found conserved from Saccharomyces cerevisiae to humans. In baker''s yeast, Zip3p has been implicated in synaptonemal complex (SC) formation, while little is known about the protein''s function in multicellular organisms. We report here the successful targeted gene disruption of zhp-3 (K02B12.8), the ZIP3 homolog in the nematode Caenorhabditis elegans. Homozygous zhp-3 knockout worms show normal homologue pairing and SC formation. Also, the timing of appearance and the nuclear localization of the recombination protein Rad-51 seem normal in these animals, suggesting proper initiation of meiotic recombination by DNA double-strand breaks. However, the occurrence of univalents during diplotene indicates that C. elegans ZHP-3 protein is essential for reciprocal recombination between homologous chromosomes and thus chiasma formation. In the absence of ZHP-3, reciprocal recombination is abolished and double-strand breaks seem to be repaired via alternative pathways, leading to achiasmatic chromosomes and the occurrence of univalents during meiosis I. Green fluorescent protein-tagged C. elegans ZHP-3 forms lines between synapsed chromosomes and requires the SC for its proper localization.

Dimitriadi M et al. (2016) Proc Natl Acad Sci U S A "Decreased function of survival motor neuron protein impairs endocytic pathways."

Maginnis MS, Atwood WJ, Nguyen KC, Kalloo G, Poulogiannis G, Hart AC, Derdowski A, Dimitriadi M, Cook SJ, Sorkac A, O'Hern P, Bliska B, Hall DH

[Proc Natl Acad Sci U S A, 2016]

Spinal muscular atrophy (SMA) is caused by depletion of the ubiquitously expressed survival motor neuron (SMN) protein, with 1 in 40 Caucasians being heterozygous for a disease allele. SMN is critical for the assembly of numerous ribonucleoprotein complexes, yet it is still unclear how reduced SMN levels affect motor neuron function. Here, we examined the impact of SMN depletion in Caenorhabditis elegans and found that decreased function of the SMN ortholog SMN-1 perturbed endocytic pathways at motor neuron synapses and in other tissues. Diminished SMN-1 levels caused defects in C. elegans neuromuscular function, and smn-1 genetic interactions were consistent with an endocytic defect. Changes were observed in synaptic endocytic proteins when SMN-1 levels decreased. At the ultrastructural level, defects were observed in endosomal compartments, including significantly fewer docked synaptic vesicles. Finally, endocytosis-dependent infection by JC polyomavirus (JCPyV) was reduced in human cells with decreased SMN levels. Collectively, these results demonstrate for the first time, to our knowledge, that SMN depletion causes defects in endosomal trafficking that impair synaptic function, even in the absence of motor neuron cell death.

Kathleen Estes et al. (2007) International Worm Meeting "C. elegans vulva development as a model for determining the role of UNC-6 Netrin in tissue morphogenesis."

Kathleen Estes, Wendy Hanna-Rose

[International Worm Meeting, 2007]

UNC-6 Netrin is a well-studied axon guidance molecule. Recently, this protein has been observed acting in morphogenesis of different tissues1. C. elegans unc-6 mutants have a well documented egg-laying defect2. Interestingly, a vulva morphology defect has also been reported but not well-characterized2. We are currently conducting an in-depth phenotypic analysis of the vulva morphology defect in various unc-6 alleles. We are also examining unc-40, the only one of the two well-characterized unc-6 receptors to exhibit an egg-laying defect2. In our initial analysis using an apical junction marker, we have found that the dorsal vulva toroid of unc-6 mutants is severely misshapen and does not seem to display this marker. We also have preliminary data suggesting the anchor cell may not invade the basement membrane, which may contribute to the vulva morphology defect. By studying the phenotype of unc-6 and unc-40 mutants in C. elegans vulva morphogenesis, we can examine this new role of netrin in tissue morphogenesis. 1. reviewed in Baker, et. al. 2006. Curr Opin Neurobiol 16: 529-534 2. Hedgecock, et. al. 1990. Neuron 2: 61-85.

Au C et al. (2008) Neurotoxicology "Manganese transport in eukaryotes: the role of DMT1."

Au C, Benedetto A, Aschner M

[Neurotoxicology, 2008]

Manganese (Mn) is a transition metal that is essential for normal cell growth and development, but is toxic at high concentrations. While Mn deficiency is uncommon in humans, Mn toxicity is known to be readily prevalent due to occupational overexposure in miners, smelters and possibly welders. Excessive exposure to Mn can cause Parkinson''s disease-like syndrome; patients typically exhibit extrapyramidal symptoms that include tremor, rigidity and hypokinesia [Calne DB, Chu NS, Huang CC, Lu CS, Olanow W. Manganism and idiopathic parkinsonism: similarities and differences. Neurology 1994;44(9):1583-6; Dobson AW, Erikson KM, Aschner M. Manganese neurotoxicity. Ann NY Acad Sci 2004;1012:115-28]. Mn-induced motor neuron diseases have been the subjects of numerous studies; however, this review is not intended to discuss its neurotoxic potential or its role in the etiology of motor neuron disorders. Rather, it will focus on Mn uptake and transport via the orthologues of the divalent metal transporter (DMT1) and its possible implications to Mn toxicity in various categories of eukaryotic systems, such as in vitro cell lines, in vivo rodents, the fruitfly, Drosophila melanogaster, the honeybee, Apis mellifera L., the nematode, Caenorhabditis elegans and the baker''s yeast, Saccharomyces cerevisiae.

Kao AW et al. (2011) Proc Natl Acad Sci U S A "A neurodegenerative disease mutation that accelerates the clearance of apoptotic cells."

Cabello J, Kao AW, Neukomm LJ, Farese RV, Eisenhut RJ, Huang A, Bagley JA, Martens LH, Nakamura A, Zhou P, de Luis A, Kenyon C

[Proc Natl Acad Sci U S A, 2011]

Frontotemporal lobar degeneration is a progressive neurodegenerative syndrome that is the second most common cause of early-onset dementia. Mutations in the progranulin gene are a major cause of familial frontotemporal lobar degeneration [Baker M, et al. (2006) Nature 442:916-919 and Cruts M, et al. (2006) Nature 442:920-924]. Although progranulin is involved in wound healing, inflammation, and tumor growth, its role in the nervous system and the mechanism by which insufficient levels result in neurodegeneration are poorly understood [Eriksen and Mackenzie (2008) J Neurochem 104:287-297]. We have characterized the normal function of progranulin in the nematode Caenorhabditis elegans. We found that mutants lacking pgrn-1 appear grossly normal, but exhibit fewer apoptotic cell corpses during development. This reduction in corpse number is not caused by reduced apoptosis, but instead by more rapid clearance of dying cells. Likewise, we found that macrophages cultured from progranulin KO mice displayed enhanced rates of apoptotic-cell phagocytosis. Although most neurodegenerative diseases are thought to be caused by the toxic effects of aggregated proteins, our findings suggest that susceptibility to neurodegeneration may be increased by a change in the kinetics of programmed cell death. We propose that cells that might otherwise recover from damage or injury are destroyed in progranulin mutants, which in turn facilitates disease progression.