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“Lmx1a is a master regulator that caninduce the generation of dopamineneurons when expressed outside of itsnormal expression domain,” Perlmannand Ericson explain. “It is functioningat the very top of the hierarchy andinitiates the regulatory cascade thatultimately leads to the generation offully mature dopamine neurons in apermissive territory.”

Although these data do not excludethe participation of other genes,especially at the final differentiationsteps, other experts on earlydevelopment of the CNS recognise therelevance of the discovery. MartenSmidt (Rudolf Magnus Institute ofNeuroscience, Utrecht, Netherlands)

said “Lmx1a seems to be a genuineintrinsic factor that drives the initialinduction process leading to a midbraindopaminergic phenotype. It would beinteresting now to see whichdopaminergic subtype is induced”.Eduardo Puelles (Instituto deNeurociencias, Alicante, Spain) agreesthat “these data might be crucial indesigning therapeutic replacementstrategies based on stem cells.”

“Importantly—since obtainingauthentic dopamine neurons is aprerequisite for cell replacementtherapy in PD—we have also shownthat when Lmx1a is expressed inmouse embryonic stem cells, bona fidedopamine neurons could be generated

in cell culture”, said the authors. “It willbe necessary now to focus intenseefforts on transferring the method tohuman embryonic stem cells.” Theyalso caution that “although some ofthe previous clinical trials using fetalhuman cells for transplantation haveshown promising result, the picture ismixed, as other trials have failed. Tomove forward towards a more robuststem cell-based therapy, authenticdopamine neurons must first begenerated and we are happy that ourresearch on basic developmentmechanisms has provided animportant step towards this goal.”

Elena Becker-Barroso

http://neurology.thelancet.com Vol 5 March 2006 207

Alpha-fetoprotein (AFP) has a role insexual differentiation of the brain, butwhether this protein protects femalebrains from the masculinising effectsof oestrogens or whether it activelytransports oestrogens into femalebrains was unclear. Now, researchershave created a mutant mouse lackingAFP in which to test these twoopposing theories. “We have providedincontrovertible proof that AFPprotects the female brain from becom-ing masculinised and defeminised byoestrogens”, says lead author JulieBakker (University of Liège, Belgium).

Bakker and colleagues assessed thesexual behaviour and sex differencesin certain areas of the brain in femaleAFP knock-out mice (Nat Neurosci2006; 9: 220–26). They found thatfemale mice homozygous for theknock-out showed little or no typicalfemale behaviour compared withheterozygous or wild-type littermates,and in fact showed signs of typicalmale behaviour. To see what effectlack of AFP had on the brains of femaleAFP�/� mice, the researchers examinedthe anteroventricular nucleus of thepreoptic region (AVPv), an area of thebrain that is critical for female repro-ductive function. Normal females have

more neurons expressing tyrosinehydroxylase in this area of the brainthan males. However, the numbers ofneurons were similar in both AFP�/�

female mice and wild-type males.To confirm the role of AFP in

protecting female brains from oestro-gens, Bakker and colleagues blockedoestrogen production during prenataldevelopment by treating pregnantmice with 1,4,6-androstatriene-3,17-dione, which blocks the conversion oftestosterone to oestradiol. This treat-ment rescued female sexual behaviourand prevented the decrease in neuronsexpressing tyrosine hydroxylase in theAVPv. “The fact that the femalephenotype of the AFP�/� mice could berescued . . . shows that oestrogens arenormally circulating in high concen-trations in fetal blood and that AFPprotects the female brain from theseoestrogens by sequestering them andpreventing them from enteringneurons”, concludes Bakker.

“An interesting implication of thisstudy is that there are sufficientoestrogens circulating in the blood ofa female, just before or after birth, tocause nearly complete masculinedifferentiation of the brain”,comments Arthur Arnold (University

of California, Los Angeles, CA, USA).However, he adds, “It is not knownwhat, if anything, protects the humanbrain from maternal oestrogens, orindeed if such protection is required.The reigning idea is that in humans,androgens, not oestrogens, are theprimary cause of brain masculinisationin males”. Geert de Vries (University ofMassachusetts, MA, USA) adds: “Iwould be surprised that there wouldnot be similar factors, perhaps inter-acting with androgens, that controldifferentiation in the human brain.”

Rebecca Love

Alpha-fetoprotein protects female brains from oestrogens

Female brains are protected from maternal oestrogens

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