Differential Song Deficits after Lentivirus-Mediated Knockdown of FoxP1, FoxP2, or FoxP4 in Area X of Juvenile Zebra Finches

Abstract

Mutations in the transcription factors FOXP1 and FOXP2 are associated with speech impairments. FOXP1 is additionally linked to cognitive deficits, as is FOXP4. These FoxP proteins are highly conserved in vertebrates and expressed in comparable brain regions, including the striatum. In male zebra finches, experimental manipulation of FoxP2 in Area X, a striatal song nucleus essential for vocal production learning, affects song development, adult song production, dendritic spine density, and dopamine-regulated synaptic transmission of striatal neurons. We previously showed that, in the majority of Area X neurons FoxP1, FoxP2, and FoxP4 are coexpressed, can dimerize and multimerize with each other and differentially regulate the expression of target genes. These findings raise the possibility that FoxP1, FoxP2, and FoxP4 (FoxP1/2/4) affect neural function differently and in turn vocal learning. To address this directly, we downregulated FoxP1 or FoxP4 in Area X of juvenile zebra finches and compared the resulting song phenotypes with the previously described inaccurate and incomplete song learning after FoxP2 knockdown. We found that experimental downregulation of FoxP1 and FoxP4 led to impaired song learning with partly similar features as those reported for FoxP2 knockdowns. However, there were also specific differences between the groups, leading us to suggest that specific features of the song are differentially impacted by developmental manipulations of FoxP1/2/4 expression in Area X.

Divergent low-density lipoprotein receptor (LDLR) linked to low VSV G-dependent viral infectivity and unique serum lipid profile in zebra finches

“…VSV G-based transgenesis in finch compared to chicken and quail (12,14), two species with an intact LDLR. We also note that even in studies reporting behavioral effects from brain gene manipulations using VSV G LVs in finches, the number of infected cells is typically quite low (15)(16)(17).…”

Dynamic FoxP2 levels in male zebra finches are linked to morphology of adult-born Area X medium spiny neurons

“…The FoxP2 protein coding sequence is highly conserved between humans and songbirds as are the brain expression patterns, notably in the cerebellum and striatum [5][6][7] . Moreover, genetic manipulations of FoxP2 expression levels in the striatal song nucleus Area X during the critical phase of song learning lead to inaccurate and incomplete imitation of the tutor's song and more variable vocal production 3,[8][9][10] . This phenotype bears similarities to the specific speech deficits called developmental verbal dyspraxia, DVD (or childhood apraxia of speech), that patients carrying FOXP2 mutations suffer from.…”

Heterozygous variants that disturb the transcriptional repressor activity of FOXP4 cause a developmental disorder with speech/language delays and multiple congenital abnormalities

“… 10 , 42 A recent study linking FoxP1/2/4 functions to vocal learning in songbirds suggested that FOXP4 should also be considered as a candidate for involvement in vocal disorders. 43 Indeed, all individuals with likely pathogenic FOXP4 variants in our study had delayed speech/language development, with expressive problems prominently present. As FOXP1, FOXP2, and FOXP4 show partially overlapping coexpression in various different regions of the developing brain, 10 further research is needed to delineate if loss-of-function of FOXP4 directly impairs speech/language development, or whether secondary disruption of FOXP1 and/or FOXP2 function via heterodimerization with dysfunctional FOXP4 could play a role as well.…”