That speech and language are innate capacities of the human brain has long been widely accepted, but only recently has an entry point into the genetic basis of. Abstract. That speech and language are innate capacities of the human brain has long been widely accepted, but only recently has an entry point into the. REVIEWS FOXP2 AND THE NEUROANATOMY OF SPEECH AND LANGUAGE Faraneh Vargha-Khadem*, David G. Gadian*, Andrew Copp* and Mortimer.

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FOXP2 and the neuroanatomy of speech and language – Semantic Scholar

Log In Sign Up. FOXP2 and the neuroanatomy of speech and language. The discovery of a mutation in FOXP2 in a family with a speech and language disorder has enabled neuroscientists to trace the neural expression of this gene during embryological development, track the effects of this gene mutation on brain structure and function, and so begin to decipher that part of our neural inheritance that culminates in articulate speech.

VERBAL DYSPRAXIA Speech and language disorders have long been known Behavioural phenotype An impaired ability to perform to run in families, and the mutation of one or more The KE family first came to the attention of the scientific the coordinated movements that genes has therefore been thought to be a likely cause in community in with the publication of a report are required for speech.

This discovery has language disorder as a developmental verbal dyspraxia2. Impairment of speech and opened a fascinating new chapter in the neurogenetics The disorder was described as one that affected the verbal comprehension. The expression and articulation of language more than its new chapter began with an investigation of three gener- comprehension, and problems were noted with orga- ations of the KE family, half of whose members have a nizing and coordinating the high-speed movements VERBAL DYSPRAXIA that is inherited in a pattern consistent that are necessary for the production of intelligible with an autosomal dominant mutation.

There were no hearing problems or neurological dyspraxia was later shown — on the basis of behavioural deficits that affected limb movements, and there was no analysis — to be rooted in an orofacial movement disor- evidence of difficulty with feeding or swallowing during der that is manifested most strikingly during speech. Later that year, several investigators published This quantitatively based description of the phenotype three further reports.

Although there is still much to ical and language-production systems rather than in Hospital for Children, 30 be learned about this neuropathology and its functional grammar 4; and the third classified it as a severe speech Guilford Street, London consequences, a good start has been made in under- disorder that interfered non-selectively with all aspects WC1N 1EH, UK. Building 49, Suite 1B, members, the correlated structural and functional One of the main aims behind identifying the core 49 Convent Drive, Bethesda, neuropathology, and the expression of the FOXP2 gene deficits was to obtain a reliable, quantitative index of MarylandUSA.

The comparison indicates that the two groups show equal deficits in manipulation of morphological markers, and, therefore, that the deficit is independent of age at onset of pathology, and independent of word meaning. However, there are also important differences between the two groups. Modified, with members are severely impaired on both types of re- permission, from REF.

On almost every test of speech and words before the onset of their aphasia.

FOXP2 and the neuroanatomy of speech and language.

The difference language that was administered 6,7, the group of family was reversed on tests of semantic, phonemic and writ- members fopx2 was presumed to be affected was, on ten fluency, on which the affected langusge ily m flxp2 bers average, significantly impaired relative to the group that were significantly less impaired than the aphasic indi- was presumed to be unaffected.

These tests included viduals, suggesting that early plasticity might have led assessments of pronunciation, grammar, semantics, to partial but significant com pensation for word verbal IQ and even non-verbal IQ, with deficits tending retrieval difficulties imposed by their developmental to be greater for measures of language production than disorder.

Performance on these guage disorder of the affected members. However, it is movements. The validity of the classi- consequences of this fundamental deficit, or whether Severe impairment of verbal expression by speech or writing fication was confirmed when it led to localization of the they point instead to the existence of additional core due to pathology of the left SPCH1 gene to the long arm of chromosome 7 Tye. Neural phenotype who discovered the relationship.

Together, these approaches can with the formation of one word vowel combinations Tasks that involved the imitation provide information about both the neuropathological from another by the addition of a prefix or suffix, often to change of non-speech movements yielded the same gradient of basis of impaired function and the neural sites that the case, gender, number or impairment, with parallel and sequential movements underlie preserved or reorganized function.

For this reason, three- so-called spin-lattice relaxation of rapid orofacial movements. Affected family members dimensional T1-WEIGHTED MRI datasets were acquired and time T1 of the protons that give rise to the MRI signals; such showed no deficits in manual praxis13, although this analysed using voxel-based morphometry VBMa images provide good contrast might be because only highly skilled movement computational technique that was developed to identify between grey and white matter.


Moreover, the volume of the caudate nuclei correlated The gene that is responsible for the speech and language disorder in the KE family was significantly with the performance of affected family originally localized to the long arm of chromosome 7 7q31 The correlations on the first two significant. Further analysis narrowed the region genetically, and identified an tests suggest a relationship between the abnormal unrelated individual, C.

Ultimately, it was in oromotor control and articulation seen in the KE analysis of the chromosomes of C.

The translocation breakpoint in C. They disrupted the genetic structure of FOXP2. Moreover, a neuroanaotmy elsewhere in the found abnormally low levels of grey matter in the infe- FOXP2 sequence was found in members of the KE family. Importantly, the mutation substituted a histidine for an arginine By contrast, there were abnormally high levels of grey at site in the FOXP2 sequence. A mutation at sperch corresponding residue, RH, in FOXC1 has Functional neuroimaging studies have also been severe consequences for protein function in vitro The images are compared on a members showed a more posterior and more exten- voxel-by-voxel basis, neuuroanatomy the final outcome displayed as sively bilateral pattern of activation in all znd.

This method can also be used to correlate indicated that, compared with the unaffected family behavioural or other variables with regional grey or members, the affected members had significantly less white matter density. By considered to provide initial hypotheses.

On the basis of the behavioural phenotype contrast, affected individuals showed overactivation evidence that linkage exists. It was also proposed occipital regions. This overactivation might reflect BAC. A vector containing an that the pathology would be bilateral — were it uni- recruitment of compensatory circuits, use of an alter- origin of replication that enables lateral the expectation, for a neurodevelopmental native strategy or simply extra cognitive effort or genomic or other DNA disorder such as this, would be that reorganization to attention that the affected family members required to fragments, inserted into the vector, to be grown in bacteria.

The initial of events through which a point mutation in the related genes, the FOX genes. VBM analyses7,14 showed bilateral abnormalities in FOXP2 gene results in the speech and language dis- FOX proteins regulate the speech of target genes by several motor-related regions, including the caudate order shown by the KE family.

They indicate ths binding their regulatory DNA nucleus, which was of particular interest because this FOXP2 might be important for the development of sequences.

This binding is structure also showed functional abnormalities in a putative frontostriatal and frontocerebellar networks performed by a special protein related positron emission tomography PET study7. A that are involved in the learning, planning and execu- structure, the winged helix, which is encoded by the more detailed volumetric analysis confirmed that both tion of neuroanaatomy and, particularly, speech motor forkhead DNA sequence in the caudate nuclei were reduced in volume by about sequences, similar to the networks involved in learning FOX gene.

Hence, the transcriptional repressor functions of FOXP1, 2 and 4 might depend neutoanatomy synergistic mole- cular functions. Reduced FOXP2 function might compromise the formation of sufficient hetero- dimers of a type required to activate downstream pat- terns spsech developm ent.

Nevertheless, the striking speech and language phenotype seen in humans with FOXP2 neuroaantomy provides evidence against signifi- cant redundancy of function, at least in this aspect of neural activity. The Foxp2 mRNA signal appears embry- protein monomer, are held cription 19, Neuroxnatomy is expressed not only in the brain, ologically in the inner layer of the cortical plate of all fetal together by hydrophobic interactions between leucine but also in other organs, including the lungs, heart and mammals that have been investigated19,21—24, with a trend residues.

The leucine zipper gut 1, It functions in the lungs during embryonic towards greater expression in lateral than in medial allows protein dimerization development to inhibit the expression of genes associ- aspects of the plate Subsequently, in newborn and pairingwhich is necessary for ated with the differentiation of pulmonary epithelial mature rodents, Foxp2 is expressed in a sub-population the DNA-binding activity of cells. In the motor system, Foxp2 is These are distinguishable How Foxp2 acts as a gene regulator in the brain is still expressed at many levels of the neuraxis.

Other basal ganglia structures that rich in opiate receptors and fetus21,22,24 between the ages of 6 and 22 weeks. For mouse at all ages21, The gene is also expressed in basal fibres.

A weaker signal is also observed in the mantle layer of the midbrain MB. Reproduced, with permission, from REF. In expression is often specific to certain subdivisions or the hindbrain, it is expressed in the cerebellum and infe- types of neuron. Foxp2 mRNA has also been found globus pallidus24, the Purkinje cells and deep nuclei of in the spinal cord of the embryonic mouse Just as it is unclear why mutation of FOXP2 in the Box 2 FOXP2 in songbirds KE family affects the development and maintenance of brain tissue but not, apparently, that of other tissues in Songbirds, like humans, learn vocalizations through imitation, raising the question of which it is expressed, so is it unclear why the KE muta- whether there are any similarities between the different versions of FOXP2 in such widely divergent species.

Recent reports24,25 indicate that there are. Although mammals and birds tion seems to affect some brain regions in which FOXP2 separated from a common line more than million years ago, the FoxP2 protein in the is expressed but not others.


Moreover, the overall gent statistical criteria than the ones adopted in these pattern of FoxP2 expression in the brain of the zebra speefh is remarkably similar to the studies might have led to the inclusion of other areas of pattern in mammalian brains, including the brain of the human fetus see text.

Nevertheless, several of the regions that Of particular interest is the expression of FoxP2 ahd the avian song circuit. The more strongly express the gene — notably a subset of lateral rostral of the two pathways that make up this circuit forms a loop homologous to the frontal and lateral temporoparietal cortical areas, and frontal—basal ganglia loop shown in FIG. Also noteworthy is neural circuitry that underlies normal speech is similar, the finding that the expression of FoxP1, unlike that of FoxP2 with which FoxP1 can in broad outline, to that determined for other motor dimerizeis sexually dimorphic, showing enhanced expression in area X of the song- functions FIG.

This circuitry enables the motor cortex learning male but not in the comparable region of the non-song-learning female. This to be modulated and controlled by other frontal cortical finding indicates that FoxP1 could also be languaage for human speech. The proposed model differs, in this respect, from a model for skilled sequential movements of the limbs.

Red arrows, inferior frontal—basal ganglia loop; blue arrows, inferior frontal—cerebellum loop. Blue and green normal or abnormal influence of all of its cortical languabe boxes indicate structures that express FOXP2; blue boxes subcortical inputs to the orofacial musculature. Suggestions for further research Many of the findings that we have discussed in this and indirectly, through two parallel cortico-subcortical review lead to suggestions for further research.

Perhaps pathways — one frontostriatal and the other fronto- the most important outstanding behavioural question is cerebellar 28— The possibility that there are to express Foxp2. Several other structures belonging to one or more further core deficits merits careful investi- the two parallel loops shown in the figure also express gation. Given the behavioural phenotype of the KE Foxp2 see figure legend. It is not known whether such mutation, candidates for independent core deficits widespread expression in motor-related structures include rule-based learning, lexical acquisition and reflects the importance of this gene in the functioning of retrieval, and non-verbal cognition.

However, the verbal all body musculature or only parts of it, but the KE dyspraxia itself needs to be examined further using such family gene mutation clearly impairs the function of the methods as electropalatography — a system for record- orofacial musculature, particularly for movement ing tongue—palate contact during speech — to identify sequences. Consistent with these findings, neuroimaging precisely the sources of misarticulation. Until issues such as The abnormalities neuronaatomy these two areas lie on either side of, these are investigated, we cannot be confident that current and possibly involve, the ventral premotor cortex in the interpretations regarding the behavioural effects of the region of the frontal operculum.

FOXP2 – Wikipedia

All three areas — FOXP2 mutation are correct. By contrast, standing of the links between the genetic abnormality and there were no apparent abnormalities in the supplemen- the behavioural profiles of affected KE family members.

Moreover, different human populations show essentially no variations in amino acid sequence, indicating that the nehroanatomy FOXP2 laanguage is fixed in modern humans. Although a number of nucleotide changes have accumulated in FOXP2 since the human and mouse lineages diverged, around 70 million years ago, only three amino acids have changed in the FOXP2 sequence.

FOXP2 and the neuroanatomy of speech and language

Strikingly, two of these three changes threonine to asparagine at position and asparagine to serine at position are present uniquely in humans, neuroanatommy not in chimpanzees, gorillas or orangutans. Hence, these amino acid substitutions arose and became fixed in the FOXP2 sequence since the human lineage diverged from the chimpanzee lineage, only 4 to 6 million years ago.

This rate of amino acid change is significantly greater than that expected by chance, given this period of evolutionary time42, Indeed, it has been estimated that the spread was completed within the past ,—, years42,43, close to the time that anatomically modern humans appeared.

The change at amino acid creates a potential phosphorylation site, which could affect how the protein functions as a transcriptional repressor, although whether the human FOXP2 sequence is functionally related to the speech and language capability of modern humans remains to be determined.

A further function of brain and language development. This would allow investigators to development could be combined with the structural res- determine the role of FOXP2 in the development of olution of MRI to provide a more comprehensive picture neural circuits on a region-by-region basis.

Of course, the of the pattern of brain abnormalities. However, nism that governs the localization of Foxp2 expression, an the evidence obtained should repay the effort, inasmuch issue that involves identifying the promoter elements and as FOXP2 is likely to continue to cast new light on the the proteins that bind to them.

The same is true for the still mysterious neural mechanisms of human oral downstream molecular events that are regulated by communication. Neural basis of an inherited speech The most recent and comprehensive description of Monaco, A.