Morris JZ et al. (1995) International C. elegans Meeting "MAPPING AND CLONING daf-23"

Ruvkun GB, Morris JZ

[International C. elegans Meeting, 1995]

The dauer formation pathway requires the animal to assimilate environmental inputs (food, pher- omone, and temperature) and regulate its dev- elopment (as a dauer or an L3 larvae) accordingly. We are cloning the gene daf-23, a maternal effect dauer constitutive gene which acts in the daf-23/ daf-2/daf-16/daf-18 branch of the dauer genetic epistasis pathway. This branch has dramatic effects on senescence as well as on dauer form- ation. Unlike the other branches of the dauer pathway, this branch has no known pleiotropies, suggesting that it acts downstream of the sensory neurons, perhaps in secretory neurons or in down- stream tissues.

Morris JZ et al. (2000) Science "Development. PARallels in axis formation."

Morris JZ, Lehmann R, Navarro C

[Science, 2000]

The anterior-to-posterior axis of a frutfly or worm embryo is determined even before the first division of the fertilized egg. As the embryo undergoes successive cell divisions, cells at one end are destined to produce anterior structures (such as the fly head or worm pharyngeal muscle cells), whereas cells at the other end are destined to produce posterior structures (such as the germ cells that give rise to egg and sperm).

Morris JZ et al. (1996) Nature "A phosphatidylinositol-3-OH kinase family member regulating longevity and diapause in Caenorhabditis elegans."

Tissenbaum HA, Morris JZ, Ruvkun GB

[Nature, 1996]

A pheromone-induced neurosecretory pathway in Caenorhabditis elegans triggers developmental arrest and an increase in longevity at the dauer diapause stage. The gene age-1 is required for non-dauer development and normal senescence. age-1 encodes a homologue of mammalian phosphatidylinositol-3-OH kinase (PI(3)K) catalytic subunits. Lack of both maternal and zygotic age-1 activity causes dauer formation, whereas animals with maternal but not zygotic age-1 activity develop as non-dauers that live more than twice as long as normal. These data suggest that phosphatidylinositol signalling mediated by AGE-1 protein controls lifespan and the dauer diapause decision.

Morris JZ et al. (1996) East Coast Worm Meeting "THE C. elegans PHOSPHATIDYLINOSITOL 3-KlNASE HOMOLOGUE AGE-1 REGULATES DAUER ARREST AND SENESCENCE"

Ruvkun GB, Morris JZ, Tissenbaum HA

[East Coast Worm Meeting, 1996]

A pheromone-induced neurosecretory signaling system in C. elegans triggers an arrest of development and of senescence at the dauer stage. age-1 is a key gene in this neuroendocrine pathway whose activity is required for both nonarrested development and normal senescence. We present evidence that age-1 is the same gene as daf-23 and that ag-1 encodes a member of the family of phosphatidylinositol 3-kinase (PI 3-kinase) catalytic subunits. Four age-1 mutant alleles affect this PI 3-kinase homologue: two lesions are stop codons that truncate the protein at distinct locations N terminal to the kinase domain and thus are likely to define the age-l null phenotype. Maternal age-1 activity is specifically abrogated in one age-1 mutant which was isolated on the basis of its enhanced longevity. Lack of either maternal or zygotic age-1 gene activity confers long life span but not developmental arrest whereas lack of both maternal and zygotic activity causes arrest at the dauer stage. These data suggest that decreased AGE-1-mediated phosphatidylinositol(3,4,5)P3(PIP3) signaling leads to increased longevity, whereas complete lack of this signaling leads to developmental arrest.

Zhao C et al. (1993) Worm Breeder's Gazette "Cloning of the lin-32 Gene"

Emmons SW, Zhao C

[Worm Breeder's Gazette, 1993]

Cloning of the lin-32 gene Connie Zhao and Scott W. Emmons, Department of Molecular Genetics, Albert Einstein College of Medicine, 1300 Morris Park Ave., Bronx, NY 10461

Emmons SW et al. (1994) Worm Breeder's Gazette "Strain Names for non-C. elegans Species."

Emmons SW, Fitch DHA, Leroi AM

[Worm Breeder's Gazette, 1994]

Strain names for non-C. elegans species Scott W. Emmonst, Armand Leroit, and David Fitch, Department of Molecular Genetics, Albert Einstein College of Medicine, 1300 Morris Park Ave., Bronx, NY 10461, Department of Biology, New York University, RmlOO9 Main Bldg., Washington Square, New York, NY 10003

Harris LJ et al. (1983) Worm Breeder's Gazette "Tc1(Hin): a variant Tc1 in C elegans."

Morris JZ, Mawji NR, Rose AM, Harris LJ

[Worm Breeder's Gazette, 1983]

Rose, et al., (1982) previously described a RFLD (restriction fragment length difference) that mapped to linkage group I, and that resulted from the insertion of a transposon into the BO strain. Genomic blot hybridization and restriction mapping demonstrated that our transposon was (almost) identical to the Tc1 characterized by Emmons, et al., (1982) with the exception that ours contained a HindIII site which was absent in Tc1 . We have now sequenced a portion of the Tc1(Hin), and find 2 nucleotide changes in the 200 or so, base pairs that we have examined. One of these changes generates a HindIII site at position 1310 in the published Tc1 sequence ( Rosenzweig, et al., 1983). Tc1(Hin) is inserted (not surprisingly) into an A/T rich region of linkage group I. We are hoping to use the Hind III restriction site as a genetic marker to follow mobility of this transposon.

Ni, J. et al. (2017) International Worm Meeting "The triggering mechanism of C. elegans germline nuclear RNAi at the native targets."

Ni, J., Gu, S., Kalinava, N.

[International Worm Meeting, 2017]

We wish to understand the molecular mechanisms that distinguish "self" and "non-self" DNA in the germline genome of C. elegans. Nuclear RNAi refers to a set of small RNA-guided chromatin-based gene-silencing pathways (e.g., heterochromatin formation and transcriptional silencing), and plays an essential role in genome surveillance in yeast, plants, and animals. We previously identified a large set of genomic loci that are targeted by germline nuclear RNAi in C. elegans [1,2]. The triggering mechanisms at these native targets appear to be highly complex and are poorly understood. We are using two different approaches to resolve this gap. (1) We are identifying aberrant features associated with germline nuclear RNAi-targeted transcripts. To this end, we are using an unbiased RNA-seq approach to characterize both polyA and non-polyA transcripts in both wild type and mutant animals. In addition, subcellular localization of the native target transcripts are being examined using single-molecule FISH and RNA-seq combined with biochemical fractionation. (2) We are using CRISPR-mediated genome editing to test whether the silencing responses at native targets are indeed triggered by the aberrant features that are identified in (1). To date, we have found that "self" and "non-self" transcripts differ in RNA-pocessing, as well as subcellular localization. By using CRISPR, we have identified cis-regulatory elements that are required for the silencing response. Reference: 1. Ni JZ, Chen E, Gu SG. BMC Genomics. 2014. PMID: 25534009 2. Ni JZ, Kalinava N, Chen E, Huang A, Trinh T, Gu SG. Epigenetics Chromatin. 2016. PMID: 26779286

Tissenbaum HA et al. (1995) International C. elegans Meeting "GENETIC AND MOLECULAR ANALYSIS OF daf-2 AND daf-16."

Gottlieb S, Lee L, Tissenbaum HA, Ruvkun GB, Lam F

[International C. elegans Meeting, 1995]

We have been studying the genetic interactions between the genes daf-2, daf-23 and daf-16 (Gottlieb and Ruvkun 1994). These genes either act in a branch separate from the daf-11/daf-21 and daf-7 group of the genetic epistasis pathway for dauer formation or further downstream in the pathway ( Riddle et al. 1981; Vowels and Thomas 1992; Thomas et al. 1993; Gottlieb and Ruvkun 1994). Molecular analysis of daf-2, daf-16 as well as daf-23 (see abstract by Morris et al. this meeting) will help to elucidate function (e.g. neurons vs. target tissues) as well as shed light on the complex genetic interactions of these genes.

Zhu Z et al. (2019) Eur J Med Chem "Inhibiting A toxicity in Alzheimer's disease by a pyridine amine derivative."

Zhu Z, Xu C, Yin E, Wang X, Zhang L, Yang T, Liu L, Guo Z, Zhang C

[Eur J Med Chem, 2019]

Alzheimer's disease (AD) is a neurodegenerative disorder with no radical therapy. Aggregation of amyloid -peptide (A) induced by various factors is associated with pathogenesis of AD. A pyridine amine derivative, 3-bis(pyridin-2-ylmethyl)aminomethyl-5-hydroxybenzyltriphenylphosphonium bromide (PAT), is synthesized. The inhibition of self- and metal-induced A aggregation by PAT is confirmed by thioflavine T fluorescence, circular dichroism spectroscopy, and TEM. Western blot, RT-PCR and fluorescence imaging indicate that PAT can alleviate the A-induced paralysis, reduce the production of ROS, and protect the mitochondrial function in transgenic C.elegans. Genetic analyses indicate that heat shock protein is involved in the alleviation of A toxicity. PAT also inhibits the activity of acetylcholinesterase in C.elegans. Morris water maze test shows that the memory and cognitive ability of APP/PS1 AD model mice are significantly improved by PAT. Both invitro and invivo studies demonstrate that PAT is effective in counteracting A toxicity and ameliorating cognitive functions in AD mice, and therefore a potential lead compound of anti-AD drugs.