Gene Expression

If these mice could speak

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Nick Wade in The New York Times reports on new research where they inserted human FOXP2 genes into the mouse genome. Here are some of the findings:

Despite the mammalian body’s dependence on having its two FOXP2 genes work just right, Dr. Enard’s team found that the human version of FOXP2 seemed to substitute perfectly for the mouse version in all the mouse’s tissues except for the brain.

In a region of the brain called the basal ganglia, known in people to be involved in language, the humanized mice grew nerve cells that had a more complex structure and produced less dopamine, a chemical that transmits signals from one neuron to another. Baby mice utter ultrasonic whistles when removed from their mothers. The humanized baby mice, when isolated, made whistles that had a slightly lower pitch, among other differences, Dr. Enard says. Discovering that humanized mice whistle differently may seem a long way from understanding how language evolved. Dr. Enard argues that putting significant human genes into mice is the only feasible way of exploring the essential differences between people and chimps, our closest living relatives.

It isn’t a surprise that FOXP2 has a lot of effects. Additionally it probably isn’t that surprising that the “language gene” as it is sometimes hyperbolically termed changes the way mice vocalize, it seems to have evolved in songbirds as well as the lineage leading up to humans. Mice are obviously more similar genetically to humans than birds so it shouldn’t been that surprising.

The original paper is in Cell, A Humanized Version of Foxp2 Affects Cortico-Basal Ganglia Circuits in Mice:

It has been proposed that two amino acid substitutions in the transcription factor FOXP2 have been positively selected during human evolution due to effects on aspects of speech and language. Here, we introduce these substitutions into the endogenous Foxp2 gene of mice. Although these mice are generally healthy, they have qualitatively different ultrasonic vocalizations, decreased exploratory behavior and decreased dopamine concentrations in the brain suggesting that the humanized Foxp2 allele affects basal ganglia. In the striatum, a part of the basal ganglia affected in humans with a speech deficit due to a nonfunctional FOXP2 allele, we find that medium spiny neurons have increased dendrite lengths and increased synaptic plasticity. Since mice carrying one nonfunctional Foxp2 allele show opposite effects, this suggests that alterations in cortico-basal ganglia circuits might have been important for the evolution of speech and language in humans.For a video summary of this article, see thePaperFlickfile available with the online Supplemental Data.

Here’s the discussion & the most important figure in relation to vocalization:

The fact that Foxp2hum influences ultrasonic vocalization of pups in a specific and reproducible way is of obvious interest. However, it is important to note that this influence is subtle and within the range of normal variation among mice. A relevant question is also to what extent mouse vocalization can be compared to human speech. All terrestrial mammals produce their vocalizations by an air stream from the lungs that passes the larynx and generates sounds. In most animals, oscillations of the vocal folds and/or specific structures of the vocal folds generate the sound through oscillations…Ultrasonic vocalizations in rodents are also produced by the larynx…but they are thought to derive from an aerodynamic whistle rather than vibrations of vocal cords…Nevertheless, the basic neurological and muscular systems necessary for vocalizations probably overlap to a large degree in mice and humans…Indeed, some neural circuits important for vocalization are even conserved in fish…Hence, the fact that Foxp2hum influences the structure of isolation calls in the mouse, especially since this effect is not accompanied by physiological effects outside the brain, supports the hypothesis that the two amino acid substitutions that occurred during human evolution affect aspects of speech and/or language.

The fact that Foxp2hum affects dopamine levels, dendrite morphology, gene expression and synaptic plasticity of medium spiny neurons indicates that it impacts cortico-basal ganglia circuits where medium spiny neurons in the striatum receive contextual information from the cortex and reward signals from dopaminergic neurons and send integrated signals to brain stem structures and the cortex…Several lines of evidence indicate that cortico-basal ganglia circuits could be relevant for speech and language…For example, reduced dopamine release in the striatum is positively correlated with speed and accuracy of phonological processing…activation of a part of the striatum plays a crucial role in lexical-semantic control…and patients with Huntington’s disease show – dependent on the striatal subregions affected – impairments in the retrieval of lexical information and the application of combinatorial rules…Furthermore, cortico-basal ganglia circuits and their dopaminergic modulations are crucial for song learning in birds, which is thought to resemble aspects of vocal learning in humans…This is supported by the recent finding that when FoxP2 expression is knocked down in basal ganglia of songbirds, vocal imitation is impaired…Furthermore, individuals heterozygous for a nonfunctional FOXP2 allele show structural effects and functional impairments in the striatum…supporting a role for FOXP2 in cortico-basal ganglia circuits with respect to speech and language.

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(B) Plots of acoustic parameters differing between genotypes. Measurements are averaged across days and individuals (SEM). The peak frequency (PF) refers to the frequency with the maximum amplitude in each analyzed time window of 0.21ms. Asterisks indicate significant differences between genotypes (: < 0.01; : < 0.001).

Update: My choice of terms elided some important nuance, as was brought up in the comments.

Comments

  1. #1 Coturnix
    May 28, 2009

    Hmmm, I thought the mice would speak Latin and Ancient Greek at least!

  2. #2 dreikin
    May 28, 2009

    Although these mice are generally healthy, they have qualitatively different ultrasonic vocalizations, decreased exploratory behavior and decreased dopamine concentrations in the brain suggesting that the humanized Foxp2 allele affects basal ganglia.

    (bold added)

    I wonder how that might have affected human evolution (if that same correlation isn’t limited to mice)? Humans are, popularly, characterized as inquisitive and explorers, but this important gene reduced exploratory behaviour in the mice.

  3. #3 Sigmund
    May 28, 2009

    I have to take issue with your first sentence where you describe the team as having “inserted human FOXP2 genes into the mouse genome”.
    This is actually incorrect.
    What they did was alter exon seven in two places such that it encoded two different amino acids and thus a very slightly different protein that contained amino acids corresponding to the human rather than native mouse sequence. The gene itself encompasses over 600 kb of genomic sequence and shows clear signs of regulatory elements within this sequence that have not been changed in this experiment (for instance human specific transcription factor binding sites, microRNA target sites and RNA binding protein recognition sites.) We should be a little cautious in assuming that the results they are showing give a full account of the functions of the FOXP2 gene in humans.

  4. #4 razib
    May 28, 2009

    sigmund, yeah, i thought a little about how i exactly i should phrase this. you’re right, but i honestly prefer a correction in the comments to having to refer to an exon so early ;-) people think of ‘genes’ in a very general way, not a technical manner. but you’re totally right that it is misleading insofar as a gene really is a much bigger bag than what they did here.

  5. #5 Joshua Zelinsky
    May 28, 2009

    Dreikin, it is very difficult to extrapolate that much from the mouse model to humans. It doesn’t necessarily imply that the gene reduces exploratory tendencies in humans. Aside from the complicated issues of brain formation one could easily posit a number of other explanations. For example, the mice might have more trouble getting their mother’s attention with their modified noises and so become correspondingly less willing to go far away.

  6. #6 eff
    May 29, 2009

    I wonder how these mice would do on more mouse-based communication tasks, for example, communicating that others should follow them to food, that a threat is present, or identifying family members.

  7. #7 bioIgnoramus
    May 29, 2009

    Mice like cheese, bacon and chocolate. So they have lots in common with us.

  8. #8 gaffa
    May 30, 2009

    Does anyone know if the crucial mutations in the bird gene are similar to the ones in the human gene?

  9. #9 Brent Michhael Krupp
    May 31, 2009

    I was always wondering what it was they did to those rats (and mice) in that book. Now we know!

    (http://en.wikipedia.org/wiki/Mrs._Frisby_and_the_Rats_of_NIMH)

  10. #10 AK
    June 3, 2009

    Does anyone know if the crucial mutations in the bird gene are similar to the ones in the human gene?

    No, they aren’t. Actually, there may not be any “crucial” mutations. See Parallel FoxP1 and FoxP2 Expression in Songbird and Human Brain Predicts Functional Interaction by Ikuko Teramitsu, Lili C. Kudo, Sarah E. London, Daniel H. Geschwind, and Stephanie A. White. Especially figure 2.

  11. #11 AK
    June 3, 2009

    I’ve commented further on this research here.

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