Outlook JOURNAL CLUB
TIG January 1999, volume 15, No. 1 0168-9525/99/$ – see front matter © 1999 Elsevier Science All rights reserved. 14
These two papers address the regulationof Hox gene expression in the mouseembryo. Previous work has shown thatFgfr1 null mutations disrupt gastru-lation, probably via an effect on cellmovement. Partenen et al.1 have createda series of Fgfr1 alleles leading to lesssevere phenotypes, which allow them todissect a potential role for FGF in pat-terning the anteroposterior (A–P) axis.Hypomorphic mutations, which reducethe level of Fgfr1 transcription, produceposterior truncation of the embryo andhomeotic transformations of the verte-brae similar to those seen in certain Hoxgene knockouts. This led them toanalyse the effect on Hox expression,and they show that the mesodermexpression of Hoxd4, Hoxb4 andHoxb9 is altered in a manner consistentwith the observed vertebral transfor-mations. Hoxd13 expression is alsoreduced in the limb buds, consistentwith defects in distal limb structures.FGF signalling is believed to be trans-duced through RAS–MAP kinase andPLCg pathways. Tyrosine 766 ofFGFR1 is an autophosphorylation site
that is implicated in transduction viaPLCg. Mutation of Y766 produced ver-tebral transformations in the oppositedirection to those caused by hypomor-phic mutations, suggesting that this siteis normally involved in repression of ligand-dependent FGFR1 function. It ispossible that these FGFR1 mutationsaffect Hox gene expression by alteringcell migration or proliferation. Suchalterations are not, however, observedin all mutant alleles, suggesting a moredirect involvement of FGF in A–P pat-terning. One possibility is that FGFalters the expression of Cdx genes, ver-tebrate homologues of Drosophila cau-dal. Charité et al.2 have identified CDX-binding sites within an upstreamregulatory element that can driveregionally restricted expression fromthe Hoxb8 promoter. A subfragmentcontaining four CDX-binding sites canpartially reproduce this expression pat-tern, and mutation of the sites abolishesits effect. They show that factors in E8.5embryos that bind these sites are presentin an A–P gradient, consistent with theexpression pattern of Cdx1, -2 and -4.
Supershift data also suggest that thesefactors are CDX proteins. Ectopicexpression of Cdx4 alters the expres-sion pattern of reporters driven by theCDX-binding element, and of endogen-ous Hoxb8. These results suggest that,unlike Drosophila caudal, vertebrateCDX factors are directly involved inestablishing the early expression of Hoxgenes. Although Partenen et al.1 couldnot detect significant changes in theexpression of Cdx1 and -4 in embryoscarrying a hypomorphic FGFR1 mu-tation, they did not rule out theirinvolvement in FGF-mediated regulationof Hox gene expression, as the dynamicpattern of Cdx expression makes it hardto determine whether they are affected.
Regulating Hox genes
1 Partenen, J. et al. 1998) Opposite phenotypesof hypomorphic and Y766 phosphorylation sitemutations reveal a function for Fgfr1 inanteroposterior patterning of mouse embryos.Genes Dev. 12, 2322–2344
2 Charité, J. et al. (1998) Transducing positionalinformation to the Hox genes: criticalinteraction of cdx gene products with position-sensitive regulatory elements. DeveIopment125, 4349–4358
Alison Snape
The prion hypothesis proposes that theagent responsible for the neurodegener-ative diseases of scrapie, CJD and BSE isa disease-causing isoform of the prionprotein termed PrPSc. The experimentalevidence that the prion protein and PrPgene is central to all aspects of the dis-ease is substantial with the exception ofthe phenomenon of strains. Studies onthe passage of scrapie isolates in geneti-cally inbred mice have demonstratedreproducible variation in the incubationperiod and pathology. This requiresthat the prion agent carry a heritableinformational molecule (conventionallynucleic acid). If the prion hypothesis is
correct, it must explain strains.Recently, limited evidence has begun toemerge that the phenotypic variationobserved in scrapie strains may be dueto multiple conformations of PrPSc. Thispaper demonstrates that eight differentprion strain passages in hamsters can bedistinguished by the use of a confor-mation-dependent immunoassay. Theassay relies on the observation that thebinding of antibodies to PrPSc is weakunless the molecule is denatured. Theratio of antibody binding to native anddenatured brain extracts from hamstersinfected with different strains combinedwith the concentration of prion protein
present gives a unique profile for eachstrain. Using this assay, Safar et al.1
have also correlated the incubation timeof various strains with the relativeamounts of protease-sensitive PrPSc andsuggest that the rate of clearance ofPrPSc rather than the rate of its synthesiswithin a cell determines the ultimateincubation period of the disease.Whether the variation in conformationof PrPSc and differences in the clearancerates of PrPSc can also explain the neuropathological variations associatedwith strains remains to be seen.
Prions – what a strain...
1 Safar, J. et al. (1998) Eight prion strains havePrPSc molecules with different conformations.Nat. Med. 4, 1157–1165
Mark Rogers
NEW – TIG Genetic Nomenclature GuideIf you require a copy of
The TIG Genetic Nomenclature Guide
please contact:
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