FOXP2, all sexed up

FOXP2 is the poster child of a sexy gene. In songbirds, decreasing FOXP2 renders a bird incapable of mimicking their tutor, resulting in more variable song. In humans, mutations in the gene is linked to a multitude of language and speech impairments, such as stuttering and trouble with enunciating sounds, syllables and words. There’s no doubt that FOXP2 is a central player in acquiring and producing vocalizations in both humans and mammals. It’s not surprising then that FOXP2 has been heralded “the language gene”. After the discovery that in both humans and Neanderthals, FOXP2 diverges from chimpanzees by a two amino acid difference, FOXP2 has even been touted the gene “that made us human”.

While FOXP2 has been studied across species, few studies have looked at if (and how) FOXP2 is expressed differently in males vs females. Given the inherent differences in vocal communication between the two sexes (in terms of frequency, pitch and speed of articulation; NOT how much each sex likes to talk), could FOXP2 be the cause of these differences?

The authors first looked at the amount of FOXP2 protein levels in the brains of male and female 4-day-old rats, and found lower levels in the cerebellum, amygdala, cortex and thalamus (but not hypothalamus) in females. FOXP1, a related protein, was not expressed differently between the two sexes in any of the brain areas they looked at.

Having found this difference, the authors next wanted to see if it had any functional significance. Just like human babies, newborn rat pups give out high-pitched wails when separated from their mothers. These cries are called “ultrasonic vocalizations”, and helps the mother hunt down her lost pups and retrieve them. The authors found that after separation, compared to females, male pups tended to cry out more, cry out at a lower frequency and amplitude, and that this correlates with moms preferentially retrieving the males before females.

To further see if FOXP2 is involved in this, the authors reduced FOXP2 protein levels in the pups by siRNA. Surprisingly, after siRNA treatment, males decreased their total calls and called at a higher frequency; on the other hand, females showed the opposite trend – in that they cried out more, and at a lower frequency. In short, after reducing FOXP2, males started crying out more like females, and vice versa.

This change in call pattern influenced the mom’s behavior as well. Compared to males with lower FOXP2, moms tend to preferentially retrieve “normal” male pups; the opposite effect was seen in females. The authors hence concluded that FOXP2 is a major player in mediating communication between moms and their pups, and thatdifferent protein levels may explain why moms preferentially retrieve male before female pups.

So what about humans? Using post-mortem tissue, they found lower FOXP2 RNA and protein levels in Brodmann’s area 44 in 4-year old boys compared to girls. This area contains Broca’s area, which is central to speech production. However, there was also a (large!) trend towards an increase in FOXP1 for girls over boys, although this was not significant (FOXP1 has been linked to mental retardation, as well as speech and language acquisition – source below).

What to make of all this? While it’s true that FOXP2 is expressed differently between the two sexes, it’s too early to conclude that it is a direct (and major) cause of vocalization differences seen between the two sexes. FOXP2 is a transcription factor that regulates a number of different genes – mainly those involved in the maturation of neurons. It is deeply involved with brain development, and mutations in FOXP2 can cause developmental deficiencies other than language. It’s hard to say if FOXP2 is directly acting on circuits mediating language production, or if its effects stem from inducing a broader developmental difference between the two sexes. The timetable for development between males and females is also slightly different – it would be interesting to see if FOXP2 levels even out as the pups age, or if the difference observed in pups (and humans) prevails throughout the entire lifespan.

Horn, D.*, Kapeller, J.*, Bruguès, N.R., Moog, U., Lorenz-Depiereux, B., Eck, S., Hempel, M., Wagenstaller, J., Gawthorpe, A., Monaco, A.P., Bonin, M., Riess, O., Wohlleber, E., Illig, T., Agnes-Studie, Franke, A., Spranger, S., Villavicencio Lorini, P., Seifert, W., Rosenfeld, J., Klopocki, E., Rappold, G.A.*, Strom, T.A.* (* equal contribution) (2010) Identification of FOXP1 deletions in three unrelated patients with mental retardation and significant speech and language deficits. Hum. Mutat. 31:E1851-60.

Bowers JM, Perez-Pouchoulen M, Edwards NS, & McCarthy MM (2013). Foxp2 mediates sex differences in ultrasonic vocalization by rat pups and directs order of maternal retrieval. The Journal of neuroscience : the official journal of the Society for Neuroscience, 33 (8), 3276-83 PMID: 23426656 

Image: singing mice. Source: