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THE LANCET Neurology Vol 3 March 2004 http://neurology.thelancet.com140

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The number of factors that regulateneurogenesis, cell fate, and patterningduring mammalian brain developmentseems to be expanding exponentially.In Jan 2004, five reports further char-acterised the roles of nine molecules.Such studies reveal targets for possibletherapeutic interventions, from stem-cell therapies to strategies that reduceunwanted responses to brain injury.

The fate of new cortical cellsdepends when they are “born”, becauseneurons in subsequent cortical layersare produced sequentially. “Theconventional view of neurogenesis isthat progenitors lose the competence togenerate earlier born neuronal fates asdevelopment progresses”, notes GordFishell (New York University MedicalCenter, USA). Therefore, the concern isthat adult neural progenitors areunlikely to be able to produce the fullrepertoire of neurons in the adult brain.

The latest findings from Fishell’steam “suggest an alternative to theconventional view”. Mice that lackFoxg1 had gross over-representation ofCajal-Retzius interneurons, the brain’s“firstborn” cells, whereas in vivomanipulation of Foxg1 revealed thatthis transcription repressor suppressesproduction of the earliest born cellsduring later brain development (Science2004; 303: 56–59, 48–49). “If thesefindings can be extrapolated”, Fishellspeculates, “it is possible that removalof the appropriate repressor genes fromadult neural stem cells would allowthem to reverse their developmentalclock and generate a wider array ofneuronal fates in the mature brain.”

Other factors recently implicated incell-fate decisions include Wnt proteinsand their downstream activation of�-catenin in neural-crest stem cells.This signalling pathway induces stem-cell expansion in neural, blood, and guttissues. Now, a group led by LukasSommer (Swiss Federal Institute ofTechnology, Zürich, Switzerland) hasshown that in cell culture and in mice,“Wnt/�-catenin instructs neural-creststem cells to adopt a sensory fate at theexpense of virtually all other possiblefates” (Science, 2004; published onlineJan 8, DOI: 10.1126/science.1091611).Thus, Sommer says, “Wnt is not a

general stem-cell growth factor;intrinsic differences dramatically affecthow different types of stem cellsrespond to Wnt/�-catenin”.

To create replacement therapies,the mechanisms that regulate stem-cellfate and the most suitable type of cellmust be identified, says Sommer, as thefates of transplanted cells might be cell-type specific. “It is therefore valuable toinvestigate the suitability of distinctstem-cell types for the treatment ofspecific brain diseases or injuries.”

Once neurogenesis has occurred,neurons must migrate to their appro-priate locations in the CNS or PNS.One factor expressed in postmitoticneurons is the anaphase-promotingcomplex (APC), says Azad Bonni(Harvard Medical School, Boston, MA,USA). His US and Canadian co-workers found that suppression ofCdh1, which stimulates APC, specif-ically increased axonal growth in the ratcerebellum. Use of RNA interference tosuppress Cdh1–APC in vitro and invivo created abnormalities in axonalgrowth and patterning (Science 2004;published online Jan 8, DOI: 10.1126/science.1093712).

Moreover, Bonni reports that RNAinterference of Cdh1 overrode theinhibitory effect of myelin on axonalgrowth. So, future work should test therole of Cdh1–APC after injury, hesuggests. “An important question iswhether inhibiting Cdh1–APC willpermit axons to regrow followinginjury.” A positive result might lead to

drugs that promote axonal regenera-tion after CNS injury.

Joseph Gleeson (University ofCalifornia, San Diego, USA) and histeam report that movement of neuronsdepends on the activity of the double-cortin protein, mutations in whichdisrupt human and mouse braindevelopment and cause lissencephaly.In turn, the ability of doublecortin tostabilise microtubules is impaired byprotein kinase Cdk5—other researchershave identified two alternativeinhibitory factors (Neuron 2004; 41:215–27; 203–13). In adults, Gleesonspeculates, “enhancing neuronalmigration through manipulation ofthese pathways may someday lead toimproved delivery of neural precursorsinto areas of damage”.

These reports raise the intriguinghypothesis that factors such as Foxg1and Wnt interact during development,but “this is entirely speculative”,cautions Fishell. For example, previousresearch suggests a role for Wnt in thecontrol of progenitor behaviour in thebrain. However, scientists have yet toprove even that such progenitors areindeed neural stem cells. Gleeson addsthat doublecortin is expressed alongsideFoxg1 in Cajal-Retzius cells, whichseem important for the establishmentof a protomap of the cortex, althoughthe role of doublecortin in theirmigration has yet to be tested directly.

Other signalling molecules—eg,Notch—play a part in neural stem-cellregulation, notes Sommer, whowonders whether intrinsic differencesmight exist in how neural progenitorsreact to Notch activation, depending ondevelopmental stage and location. “Inany case”, he concludes, “it is likely thatthe biological activities of moleculesregulating neural-fate decisions—suchas Wnt and Notch—are modulated by cross-talk with other signalingpathways.”

Clearly, much more needs to belearned about the differential effectsexerted by molecular factors, whilegreater understanding of the interplaybetween multiple pathways also will becrucial to realising the exciting potentialfor future therapies.Kelly Morris

Myriad molecules drive nervous-system development

Lissencephaly: when signalling pathways go bad

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