Epigenetic inheritance of coat colour

The ability to propagate stable states ofchromatin activity is essential for nor-mal animal development; however, littleis known about the mechanisms thatmaintain these heritable chromatinstates. Morgan et al.1 exploited thedominant mouse Avy mutation to lookat epigenetic inheritance at this locus.This mutation causes variable ectopicexpression of the agouti protein in hairfollicles, such that Avy offspring of Avy

animals exhibit a spectrum of coat-colour phenotypes, ranging from yellow(ectopic expression of the agouti gene)to full agouti (no ectopic silencing of

the agouti gene). Variable expression ofthe Avy allele in Avy progeny is caused by the variable activity of an adjacentretroposon. However, it is also influ-enced by the maternal phenotype: Avy

mothers with an agouti coat give birthto more offspring with an agouti pheno-type, whereas Avy mothers with a yellowcoat give birth to more offspring withyellow and mottled phenotypes.Morgan et al. found that the Avy allele ismore extensively methylated in Avy off-spring with an agouti coat than in Avy

offspring with a yellow coat, indicatingthat chromatin modifications associated

with the state of transcriptional activityat the maternal Avy allele are transmit-ted to the offspring. By embryo transferexperiments and genetic crosses,Morgan et al. excluded the maternalenvironment as a factor influencing Avy phenotypes, emphasizing the significance of the maternally transmitted chromatin modifications togene silencing at this locus.

1 Morgan, H.D. et al. (1999) Epigeneticinheritance at the agouti locus in the mouse.Nat. Genet. 23, 314–318

Vincent Cunliffe

v.t.cunliffe@sheffield.ac.uk

The serine/threonine protein kinaseGSK3 is a key component of the Wntsignalling cascade that controls cell-fatedecisions in metazoans. Binding of Wntto the Frizzled serpentine receptorsinhibits GSK3 activity, causing cyto-plasmic b-catenin to accumulate and betranslocated to the nucleus to alter genetranscription. GSK3 is often perceivedto be constitutively active or to have abasal kinase activity; however, maximalGSK3 activity requires the phosphoryl-ation of a conserved GSK3 tyrosineresidue. A recent study1 has shed lighton this activation of the GSK3 pathway.

In Dictyostelium, GSK3 activity isrequired for prespore cell differentiationand is differentially regulated by distinct

cAMP serpentine receptors (cARs).cAMP binding to cAR3 stimulates GSK3activity, whereas cAR4 negatively regu-lates GSK3 function. Together thesereceptors control axis formation inDictyostelium. In a recent paper, Kim et al.1 have identified a novel kinase,ZAK1, that is required for GSK acti-vation. ZAK1 is a cytosolic protein with a tyrosine kinase domain and a Ser/Thrkinase domain. It is activated in responseto cAR3-mediated cAMP signalling and,in turn, activates GSK3. Kim et al. havedemonstrated that the ZAK1 tyrosinekinase domain controls GSK3 function invivo and is capable of phosphorylatingand activating mammalian GSK3 in vitro.Parallels in controlling axis formation

exist between Dictyostelium and meta-zoans. In both systems, it is controlledthrough serpentine receptors (Frizzled,cAMP receptors) that regulate GSK3activity. It is possible that similaritiesextend beyond these components andthat the regulation of GSK3 activity insome metazoans may require a ZAK1-like kinase. At present, little is knownabout GSK3 activation by tyrosine phos-phorylation, and the ZAK1 pathway inDictyostelium might provide importantand novel insights into the regulation ofGSK3 for cell-fate decisions during multi-cellular development in other systemsand, potentially, into the evolution ofcell-fate regulatory networks.

Regulation of GSK3

1 Kim, L. et al. (1999) The novel tyrosine kinaseZAK1 activates GSK3 to direct cell fatespecification. Cell 99, 399–408

Richard A. Firtel

rfirtel@ucsd.edu

To determine how far the genome ofMycoplasma genitalium could bereduced without hampering its survival,Hutchison et al.1 used large-scale transposon mutagenesis to establish aminimum genome size for an indepen-dently replicating cell living under laboratory conditions. They found thatat least 129 genes in M. genitalium canbe disrupted without lethal consequences.However, what constitutes such a mini-mal genome is, of course, relative to theenvironment it requires. Assuming aPoisson distribution of transposon

insertions, the minimal gene set of M.genitalium consists of 265–350 protein-coding genes, with 180–215 non-essentialgenes, implying that at least 75% of theundisrupted genes are essential. Onemight expect that a large fraction ofessential genes would be shared withmany species – a core set of genesrequired for bacterial life. However, thedisrupted gene set contains, for ex-ample, only one ribosomal protein.Nevertheless, 42 of the genes that werenot disrupted are unique to theMycoplasmas. Such genes could

encode, for example, the Mycoplasmacytoskeleton that is unique to these bacteria. Thus, which genes constitute a minimal genome becomes a taxon-specific question, implying thatthere might be many, quite different,minimal genomes possible.

Constructing a minimal genome

1 Hutchison, C.A. et al. (1999) Global transposonmutagenesis and a minimal mycoplasmagenome. Science 286, 2165–2169

Martijn Huynen

huynen@embl-heidelberg.de

Outlook JOURNAL CLUB

TIG March 2000, volume 16, No. 3116

Epigenetic inheritance of coat colour