INT231944

Context Info Confidence 0.62 First Reported 2008 Last Reported 2010 Negated 4 Speculated 3 Reported most in Body Documents 2 Total Number 22 Disease Relevance 0.89 Pain Relevance 0.31

growth (FOXP2) nucleolus (FOXP2) nucleus (FOXP2) intracellular (FOXP2) embryo development (FOXP2) DNA binding (FOXP2)

Anatomy Link Frequency juveniles 2 striatum 2 neurons 1 brain 1 nucleus 1 FOXP2 (Homo sapiens)

Pain Link Frequency Relevance Heat melanocortin 1 receptor 13 97.08 medulla 21 84.00 anesthesia 21 5.00

Disease Link Frequency Relevance Heat Deafness 210 99.36 Targeted Disruption 21 85.52 Congenital Anomalies 42 19.96 Decapitation 42 5.00 Language Disorders 21 5.00 Ganglion Cysts 21 5.00 Death 1 5.00

Sentences Mentioned In

Key:

Protein

Mutation

Event

Anatomy

Negation

Speculation

Pain term

Disease term

The precise temporal regulation of FoxP2 that occurs only during singing, and the regional restriction of this regulation to song control nucleus area X strongly suggests that FoxP2 has a post-organizational role in learned vocalizations.

Regulation (regulation) of FoxP2 in nucleus

1) Confidence 0.62 Published 2010 Journal PLoS ONE Section Body Doc Link PMC2796720 Disease Relevance 0.14 Pain Relevance 0.04

Our findings suggest that basal FoxP2 levels are associated with structural growth of area X and are not affected by deafening.

Neg (not) Regulation (affected) of FoxP2

2) Confidence 0.62 Published 2010 Journal PLoS ONE Section Body Doc Link PMC2796720 Disease Relevance 0 Pain Relevance 0

This suggests that basal (i.e. non-singing) FoxP2 levels in area X are not regulated by auditory input during song development.

Neg (not) Regulation (regulated) of FoxP2

3) Confidence 0.62 Published 2010 Journal PLoS ONE Section Body Doc Link PMC2796720 Disease Relevance 0.07 Pain Relevance 0

Here, we report this evidence for both motor and auditory regulation of FoxP2.

Regulation (regulation) of FoxP2

4) Confidence 0.62 Published 2010 Journal PLoS ONE Section Body Doc Link PMC2796720 Disease Relevance 0 Pain Relevance 0

Thus, in cases where we observed singing-driven regulation of FoxP2 in area X using outlying striatum as a control tissue for normalization, we additionally measured FoxP2 levels in nidopallial regions of the same section (outside of LMAN) and used these for normalization.

Regulation (regulation) of FoxP2 in striatum

5) Confidence 0.54 Published 2010 Journal PLoS ONE Section Body Doc Link PMC2796720 Disease Relevance 0 Pain Relevance 0

Previously, we considered whether the singing driven down-regulation of FoxP2 observed in adults [21] was related to the stereotyped nature of these songs or, alternatively, to their ongoing subtle variability.

Regulation (regulation) of FoxP2

6) Confidence 0.45 Published 2010 Journal PLoS ONE Section Body Doc Link PMC2796720 Disease Relevance 0.12 Pain Relevance 0.04

The extent of FoxP2 down-regulation was correlated with both the amount of time spent singing (Spearman Rho p<0.02; Fig. 4 left) and with the number of motifs sung (p<0.02).

Regulation (regulation) of FoxP2

7) Confidence 0.45 Published 2010 Journal PLoS ONE Section Body Doc Link PMC2796720 Disease Relevance 0 Pain Relevance 0

However, the extent of FoxP2 down-regulation in juveniles was qualitatively similar to that seen for adults [21].

Regulation (regulation) of FoxP2 in juveniles

8) Confidence 0.45 Published 2010 Journal PLoS ONE Section Body Doc Link PMC2796720 Disease Relevance 0 Pain Relevance 0

To investigate whether FoxP2 in juvenile birds exhibits behavioral regulation similar to adults [21], we allowed 75d hearing birds to sing for 2 hours and examined the FoxP2 levels in area X.

Spec (whether) Regulation (regulation) of FoxP2 in juvenile

9) Confidence 0.45 Published 2010 Journal PLoS ONE Section Body Doc Link PMC2796720 Disease Relevance 0 Pain Relevance 0

In contrast to this relatively stable expression, when juvenile birds sang, FoxP2 was acutely down-regulated in area X relative to the surrounding striatum (Fig. 3), similar to what we previously reported for adult birds [21].

Regulation (regulated) of FoxP2 in striatum

10) Confidence 0.45 Published 2010 Journal PLoS ONE Section Body Doc Link PMC2796720 Disease Relevance 0.14 Pain Relevance 0

FoxP2 regulation could contribute to these slower changes across the lifetime of the animal, a finding supported by the constant replacement of FoxP2 immunoreactive neurons in zebra finch area X [16].

Regulation (regulation) of FoxP2 in neurons

11) Confidence 0.45 Published 2010 Journal PLoS ONE Section Body Doc Link PMC2796720 Disease Relevance 0 Pain Relevance 0

Deafening of young birds either shortly before or at the onset of sensorimotor learning did not affect the basal expression pattern of FoxP2 in area X at any of the three ages tested (Fig. 2) despite the expected disruption of song development [32], [40].

Neg (not) Regulation (affect) of FoxP2

12) Confidence 0.40 Published 2010 Journal PLoS ONE Section Body Doc Link PMC2796720 Disease Relevance 0.06 Pain Relevance 0

In the latter study, chronic down-regulation of FoxP2 using RNA interference resulted in more variable songs of 90d experimental birds relative to age-matched controls.

Regulation (regulation) of FoxP2

13) Confidence 0.40 Published 2010 Journal PLoS ONE Section Body Doc Link PMC2796720 Disease Relevance 0 Pain Relevance 0

We then tested for acute down-regulation of FoxP2 in area X of 75 d birds as a function of singing for two hours in the morning.

Regulation (regulation) of FoxP2

14) Confidence 0.40 Published 2010 Journal PLoS ONE Section Body Doc Link PMC2796720 Disease Relevance 0 Pain Relevance 0

Thus, one concern was that the lack of correlation in the deafened group might be due to maximal down-regulation of FoxP2 (i.e. a ‘floor’ effect) in birds who sang a lot.

Spec (might) Regulation (regulation) of FoxP2

15) Confidence 0.40 Published 2010 Journal PLoS ONE Section Body Doc Link PMC2796720 Disease Relevance 0 Pain Relevance 0

20% of area X was affected, so presumably FoxP2 levels were normally regulated in the remaining portion.

Regulation (regulated) of FoxP2

16) Confidence 0.27 Published 2010 Journal PLoS ONE Section Body Doc Link PMC2796720 Disease Relevance 0 Pain Relevance 0

However, the extent of down-regulation depended on the amount of singing only among hearing birds (Fig. 4), suggesting multiple layers of FoxP2 regulation.

Regulation (regulation) of FoxP2

17) Confidence 0.27 Published 2010 Journal PLoS ONE Section Body Doc Link PMC2796720 Disease Relevance 0.18 Pain Relevance 0.04

Although chronic auditory deprivation during sensorimotor learning produced abnormal songs, it did not alter basal FoxP2 expression levels.

Neg (not) Regulation (alter) of FoxP2

18) Confidence 0.27 Published 2010 Journal PLoS ONE Section Body Doc Link PMC2796720 Disease Relevance 0.07 Pain Relevance 0

The persistent expression of FoxP2 observed here during late sensorimotor learning, the high levels of expression during human [14] and songbird embryogenesis [15], the FoxP2 immunoreactivity observed within newly generated neurons in area X [16], and the structural brain deficits in humans bearing FOXP2 mutations [41] are all consistent with a role for this molecule in the formation of certain brain regions, including the striatum.

Regulation (immunoreactivity) of FoxP2 in brain

19) Confidence 0.27 Published 2010 Journal PLoS ONE Section Body Doc Link PMC2796720 Disease Relevance 0 Pain Relevance 0

Krause and colleagues [19] targeted the FOXP2 sequence in two Neanderthal specimens from El Sidron, Spain (Figure 2), excavated under sterile conditions to avoid contamination, and recovered the derived form of FOXP2 identical to that found in humans.

Regulation (targeted) of FOXP2

20) Confidence 0.27 Published 2008 Journal Genome Biol Section Body Doc Link PMC2374707 Disease Relevance 0 Pain Relevance 0.19

General Comments

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