In order to bring about a correctly developed individual,the body's cells undergo an intricate, interactive dancethat ends with the right organs and tissues beingconstructed in the right place. How cells accomplish thistask continues to be the central question of developmentalbiology.

Several genes now have been identified in roundwormsand fruit flies that influence the critical cellularinteractions that occur during organ formation, ultimatelycontrolling the position of various anatomical structures.Versions of these genes also exist in mammals, such asrodents and humans, indicating that the mechanisms bywhich embryonic development occurs are highlyconserved.

One such gene family that is critical during developmentis called Notch. This gene codes for cell surface receptorsthat mediate the signaling between cells that is involvedin the determination of cell fate. Among its otherfunctions, Notch causes cells to differentiate into thosethat will form nervous tissue in fruit flies.

In a paper published in the most recent issue of Nature,dated Sept. 28, 1995, a roundworm, or nematode, genethat suppresses the functioning of lin-12, a Notch familygene, has been identified. As it turns out, one version ofthis suppressor gene is very similar to one implicated inearly-onset familial Alzheimer's disease.

The article titled, "Facilitation of lin-12-mediatedsignaling by sel-12, a Caenorhabditis elegans S182Alzheimer's disease gene," was written by Diane Levitan,of Princeton University, and Iva Greenwald, a HowardHughes Investigator at Columbia University College ofPhysicians and Surgeons.

sel-12 Similar To Early-Onset Alzheimer's Gene

These investigators used nematodes that characteristicallydeveloped multiple vulva. This characteristic, orphenotype, resulted from a mutation in the lin-12 gene,which is a member of the Notch gene family. Theytreated nematodes having this phenotype with ethylmethanesulfonate, a drug used to cause mutations. Aftertreatment, they screened for revertant worms that did nothave multiple vulva.

Using these methods, a new gene named sel-12, forsuppressor and/or enhancer of lin-12, that caused thisreversion was identified. The screen identified twoversions of this gene, named ar131 and ar133 that aresuppressors of lin-12 function. The protein that ispredicted to be encoded by sel-12 contains multiplepotential transmembrane domains, which is consistentwith its functioning as a cell surface receptor, ligand, orstructural protein.

By screening the genomes of almost 6,000 mutagenizednematodes, two additional versions, or alleles, of the newsel-12 gene were identified. Using molecular analysis, theinvestigators found that one of these, named ar171,appears to code for a truncated protein product. Searchesof gene sequence data bases revealed the surprising resultthat the predicted sequence of the sel-12 protein encodedby the ar171 allele is highly similar to S182, a mutantversion of which has been implicated in familial early-onset Alzheimer's disease.

Greenwald, a developmental geneticist, told BioWorldToday that the work reported in Nature was beingextended along two complementary pathways.

"We are trying to find suppressors of the ar171 allele.Hopefully, a known protein will be identified as a resultof this search," Greenwald said, adding that, "Thepotential here is that a system can be set up to do rapidscreening of potential drug candidates for Alzheimer'sdisease."

Greenwald also explained that, "We want to engineerchanges in genes known to be associated withAlzheimer's disease in humans. These engineered genescan then be used to generate transgenic nematode linesand then see what characteristics are modified." Notingthe short, three-day generation time of these worms, shesaid, "By using them as a model system for Alzheimer's,the analysis of phenotype changes should help give usinsight into the progression of this disease."

Robert Horvitz, a molecular geneticist at MassachusettsInstitute of Technology, told BioWorld Today that, "Thestrength of this work is that here is a gene associated witha disease that a lot of people care about and now it canmore easily be studied in a worm." n

-- Chester A. Bisbee Special To BioWorld Today

(c) 1997 American Health Consultants. All rights reserved.