Pathways to enlightenment
2
M EETING R EPORT TIG AUGUST 1998 VOL. 14 NO. 8 302 Copyright © 1998 Elsevier Science Ltd. All rights reserved. 0168-9525/98/$19.00 PII: S0168-9525(98)01536-4 Pathways to enlightenment BSDB MEETING: DEVELOPMENTAL PATHWAYS, UNIVERSITY OF LANCASTER, UK, 31 MARCH–3 APRIL 1998. The spring BSDB (organized by Paul Sharpe and Anthony Graham) pro- vided a forum for progress in under- standing ‘developmental pathways. Typical of a BSDB meeting, topics ranged widely from early embryonic patterning to the later stages of tissue development with examples from the whole range of organisms (yeast, slime mould, plants, fly, frog, fish, mouse, chick and human). The striking con- servation of signalling pathways and mechanisms was reflected by the frequent cross-organism comparisons. Setting up polarity in individual cells and tissues is critical to devel- opment. In C. elegans, for example, the mom genes (encoding WNT sig- nalling components) are required for an induction that polarizes gut potential in a four-cell stage blas- tomere called EMS (Bruce Bowerman, Univ. of Oregon, USA) 1 . WNT sig- nalling can directly polarize the cytoskeleton in the EMS cell. Bowerman pointed out that we are quick to consider the target of sig- nalling to be the nucleus but in this case, at least, it is the cytoskeleton. This WNT signalling works through Arrow, a microtubule-associated pro- tein. Another example of WNT sig- nalling leading to cytoskeletal effects is the induction of neuronal remod- elling. How do external factors reor- ganize neuronal cytoskeleton? WNT7A causes axonal spreading and branch- ing in developing neurons by reduc- ing stable microtubule formation in spreading areas (Phillip Gordon- Weeks and Patricia Salinas, The Randall Inst., UK). This effect is mediated by GSK3, a highly con- served serine/threonine kinase that is negatively regulated by WNT. A new target for GSK3b has been identified, MAP1B, which is associated with microtubules. Microtubule dynamics are altered if GSK3 cannot phos- phorylate MAP1B. Spatial patterning is induced but cells intermingle, so how are precise patterns maintained? The fly embryo prevents mingling by forming dis- tinct cell groups – segments. In ver- tebrates, once rhombomeres have formed, cell mingling is also prohib- ited. A molecular description of the phenomenon is being provided by the study of EPH receptors and their ligands (ephrins) in zebrafish development. EPH receptors and ephrins are expressed in comple- mentary domains along hindbrain segments (rhombomeres). The com- plementary pattern of receptor–ligand expression prohibits cell intermin- gling between adjacent segments and cell sorting occurs at rhombomere boundaries (David Wilkinson, Natl Inst. Med. Res., UK) 2 . The emerging view is that EPHs and ephrins have general roles in restricting the move- ment of cells and axons. Patrick Doherty (Guy’s Hosp. Medical Sch., UK) 3 introduced the concept of ‘receptor indexing’, in that cell adhesion molecules (CAMs) ellicit the correct response by activat- ing fibroblast growth factor receptors (FGFRs) as indexed by phosphoryla- tion. Interestingly, the CAM signalling pathway involved in stimulation of axonal growth does not require the adhesion function of CAMs. FGFRs are phosphorylated in response to CAMs and the idea is that CAMs clus- ter at adhesion sites, thus, bringing FGFRs together. It might be that receptors are generally not scattered randomly in the membrane but mixed and aggregated. Indeed, the generality of receptor tyrosine kinase involvement in development was reflected by the majority of talks. It is believed that segmentation arose independently between flies and vertebrates, so when David Ish- Horowicz (ICRF Labs, UK) argued that segmentation in vertebrates and flies is the same process, an animated discussion followed. cHairy1 is the chick homologue of Drosophila Hairy (a pair-rule gene). The process of segmentation (somitogenesis) involves the transcriptional repressor cHairy1, which is expressed in a wave-like pattern. cHairy1 is alter- nately transcribed in cycles with a periodicity equal to that of somitoge- nesis (every 90 min a new somite is formed at the posterior end) 4 . The periodicity of cHairy1 expression still occurs when cells are isolated (and in the presence of blockers of protein synthesis). This shows that spatial periodicity is prefigured by temporal periodicity. These are tantalizing observations but how does the clock count the 11 cycles of expression? Pattern formation can also result from a signal gradient. For example, graded SHH signalling is necessary and sufficient to generate different classes of ventral neurons in the neural tube by establishing distinct progenitor cells. PAX6 and NXK2.2 are expressed differentially in response to the SHH gradient to pre- scribe subsequent cell fate (James The BSDB Waddington Medal was designed by Rosa Beddington (NIMR, UK). Front: a snake eating its own tail represents Prof. C.H. Waddington’s feedback model of regulation. Also depicted are Drosophila wing growth zones, two pairs of chromatids and a chick egg. Back: an amonite, recalling the origins of Waddington’s life in research as a geologist. Waddington lives on in the language of development, having coined such terms as ‘induction’, ‘fate’ and ‘competence’.
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Transcript of Pathways to enlightenment
MEETING REPORT
TIG AUGUST 1998 VOL. 14 NO. 8
302Copyright © 1998 Elsevier Science Ltd. All rights reserved. 0168-9525/98/$19.00PII: S0168-9525(98)01536-4
Pathways to enlightenmentBSDB MEETING: DEVELOPMENTAL PATHWAYS, UNIVERSITY OF LANCASTER, UK, 31 MARCH–3 APRIL 1998.
The spring BSDB (organized by PaulSharpe and Anthony Graham) pro-vided a forum for progress in under-standing ‘developmental pathways.Typical of a BSDB meeting, topicsranged widely from early embryonicpatterning to the later stages of tissuedevelopment with examples from thewhole range of organisms (yeast, slimemould, plants, fly, frog, fish, mouse,chick and human). The striking con-servation of signalling pathways andmechanisms was reflected by the frequent cross-organism comparisons.
Setting up polarity in individualcells and tissues is critical to devel-opment. In C. elegans, for example,the mom genes (encoding WNT sig-nalling components) are required for an induction that polarizes gutpotential in a four-cell stage blas-tomere called EMS (Bruce Bowerman,Univ. of Oregon, USA)1. WNT sig-nalling can directly polarize thecytoskeleton in the EMS cell.Bowerman pointed out that we arequick to consider the target of sig-nalling to be the nucleus but in thiscase, at least, it is the cytoskeleton.This WNT signalling works throughArrow, a microtubule-associated pro-tein. Another example of WNT sig-nalling leading to cytoskeletal effectsis the induction of neuronal remod-elling. How do external factors reor-ganize neuronal cytoskeleton? WNT7Acauses axonal spreading and branch-ing in developing neurons by reduc-ing stable microtubule formation in spreading areas (Phillip Gordon-Weeks and Patricia Salinas, TheRandall Inst., UK). This effect is mediated by GSK3, a highly con-served serine/threonine kinase that isnegatively regulated by WNT. A newtarget for GSK3b has been identified,MAP1B, which is associated withmicrotubules. Microtubule dynamicsare altered if GSK3 cannot phos-phorylate MAP1B.
Spatial patterning is induced butcells intermingle, so how are precisepatterns maintained? The fly embryoprevents mingling by forming dis-tinct cell groups – segments. In ver-tebrates, once rhombomeres haveformed, cell mingling is also prohib-ited. A molecular description of the
phenomenon is being provided by the study of EPH receptors andtheir ligands (ephrins) in zebrafishdevelopment. EPH receptors andephrins are expressed in comple-mentary domains along hindbrainsegments (rhombomeres). The com-plementary pattern of receptor–ligandexpression prohibits cell intermin-gling between adjacent segmentsand cell sorting occurs at rhombomereboundaries (David Wilkinson, NatlInst. Med. Res., UK)2. The emergingview is that EPHs and ephrins have
general roles in restricting the move-ment of cells and axons.
Patrick Doherty (Guy’s Hosp.Medical Sch., UK)3 introduced theconcept of ‘receptor indexing’, inthat cell adhesion molecules (CAMs)ellicit the correct response by activat-ing fibroblast growth factor receptors(FGFRs) as indexed by phosphoryla-tion. Interestingly, the CAM signallingpathway involved in stimulation ofaxonal growth does not require theadhesion function of CAMs. FGFRsare phosphorylated in response toCAMs and the idea is that CAMs clus-ter at adhesion sites, thus, bringingFGFRs together. It might be thatreceptors are generally not scatteredrandomly in the membrane butmixed and aggregated. Indeed, thegenerality of receptor tyrosine kinaseinvolvement in development wasreflected by the majority of talks.
It is believed that segmentationarose independently between fliesand vertebrates, so when David Ish-Horowicz (ICRF Labs, UK) arguedthat segmentation in vertebrates andflies is the same process, an animateddiscussion followed. cHairy1 is the chick homologue of DrosophilaHairy (a pair-rule gene). The processof segmentation (somitogenesis)involves the transcriptional repressorcHairy1, which is expressed in awave-like pattern. cHairy1 is alter-nately transcribed in cycles with aperiodicity equal to that of somitoge-nesis (every 90 min a new somite isformed at the posterior end)4. Theperiodicity of cHairy1 expression stilloccurs when cells are isolated (andin the presence of blockers of proteinsynthesis). This shows that spatialperiodicity is prefigured by temporalperiodicity. These are tantalizingobservations but how does the clockcount the 11 cycles of expression?
Pattern formation can also resultfrom a signal gradient. For example,graded SHH signalling is necessaryand sufficient to generate differentclasses of ventral neurons in theneural tube by establishing distinctprogenitor cells. PAX6 and NXK2.2are expressed differentially inresponse to the SHH gradient to pre-scribe subsequent cell fate (James
The BSDB Waddington Medal wasdesigned by Rosa Beddington(NIMR, UK). Front: a snake
eating its own tail representsProf. C.H. Waddington’s
feedback model of regulation.Also depicted are Drosophila
wing growth zones, two pairs ofchromatids and a chick egg.
Back: an amonite, recalling theorigins of Waddington’s life in
research as a geologist.Waddington lives on in the
language of development, havingcoined such terms as ‘induction’,
‘fate’ and ‘competence’.
MEETING REPORT
TIG AUGUST 1998 VOL. 14 NO. 8
303
Briscoe, Columbia Univ., USA). Long-range patterning in the epithelium ofthe fly retina involves the differentialresponse to two independent orth-ogonal gradients, set up by HH andWG. Again, this WG (WNT) sig-nalling was shown to work throughArrow and Shaggy (GSK3, ZW3) toinhibit Armadillo (Andrew Tomlinson,Columbia Univ., USA).
The regulation of signalling path-ways was also discussed and a veryinteresting example is the mecha-nism of negative regulation of TGFbsignalling by anti-SMADs (JeffWrana, Univ. of Toronto, Canada; AliHemmati-Brivanlou, The RockefellerUniv., USA)5. Anti-SMADs are impor-tant in the development of neuronalfate and specific SMAD proteins arelinked to cancer. SMADs mediateTGFb signalling by transient associa-tion with TGFb type I receptors. The receptor-regulated SMADs arephosphorylated, disassociate fromthe receptors and mediate signals to
the transcriptional machinery. Anti-SMADs lack the phosphorylation sitefound in SMADs and, therefore, bindirreversibly to receptors, blockingsignalling. Anti-SMADs also blocksignalling by binding to other SMADs,thereby blocking translocation to thenucleus.
The meeting was brought beauti-fully to a close by Jeffrey Williams’(UCL, UK) dramatic video of prestalkA- and B-cell streaming in Dictyo-stelium (cells were differentiallystained with green and yellow GFP).Differentiation in Dictyostelium in-volves the DIF pheromone responseto extracellular cAMP levels, whichcauses individual cells to aggregateand form the differentiated ‘slug’ con-taining prespore A and B cells at theanterior. This signal functionsthrough a STAT pathway and multipleSTATs have recently been identifiedin Dictyostelium. STATa protein is at aconstant level during the majority ofdevelopment but becomes phospho-
rylated and localized to the nucleus inresponse to the cAMP signal.
A more personal highlight of this meeting was the award of theBSDB Waddington Medal to CheryllTickle for her life-long work on chicklimb development. The BSDBWaddington Medal is a new awardfor senior developmental biologistswho are still working at the bench.
Further reading1 Bowerman, B. (1998) Curr. Top.
Dev. Biol. 39, 73–1172 Orioli, D. and Klein, R. (1997)
Trends Genet. 13, 354–3593 Kenwrick, S. and Doherty, P.
Bioessays (in press)4 Cooke, J. (1998) Trends Genet. 14,
85–885 Kretzschmar, M. and Massague, J.
(1998) Curr. Opin. Genet. Dev. 8,103–111
Rachel WoodAssistant Editor, Trends in Genetics
LETTERS
The article by Luca Cavalli-Sforza1,in a recent issue of Trends inGenetics, is a good summary ofmuch of the work that has beendone on the genetics of humanorigins. The paper reviewsmitochondrial DNA sequence and Y chromosome studies, and itdescribes how multilocus allelicdata has been used for the estimationof historical patterns of populationmovement and splitting. Finally, asthe paper is entitled The DNArevolution in population genetics itis written as a celebration of theincreased resolution of evolutionaryquestions that is made possible byjoining population genetics with DNAdata. However, the focus is mostlyon the value of additional mendelianpolymorphisms, and the reviewoverlooks the most importantcomponent of the DNA revolution –haplotype data – particularly as ithas affected our insight into thegenetics of human origins.
For example, Cavalli-Sforzareviews how the history ofpopulations can be estimated fromallelic data, but these analyses havea fundamental weakness. In theseanalyses, the allelic data were usedto generate a numerical distancebetween each pair of populations,and it is these distance numbers thatare used to build population trees.However, any single measure ofdistance confounds divergence dueto time since populationsubdivision, and divergence due tolimited gene flow. For instance, twopopulations separated long ago, butwith regular gene flow, might wellreveal a lower numerical distancevalue than do two populationsseparated more recently but havingzero gene flow. The possibility oftwo very different histories, or of amixture that lies between theseextremes, leads to an importantdistinction between gene trees andpopulation trees. For a gene tree,
the theoretical meaning of a node, abranch point on the tree, isinvariably an ancestral DNA; whilefor a population tree a node canmean either an ancestral population(if there has been no gene flow) or,if divergence has been a function oflimited low-level gene flow, it willmean nothing! When there is geneflow, a population tree is simply agraphical representation of distances,and the parts of the tree have notheoretical correspondence tohistorical entities. The assumption ofpopulation splitting that is invokedfor the population tree analyses isespecially unfortunate within thecontext of debates about the originsof modern humans, much of whichconcerns the magnitude and role ofgene flow among populationsduring the emergence of modernhumans.
It is true that a major revolutionhas occurred for populationgenetics, but it arises from the factthat much of the DNA data comesnot in allelic form but in haplotypeform. These data increasingly comeas sets of multiple alignedhomologous DNA sequences from
Population genetics and human origins –haplotypes are key!
