Differential Gene Expression in the Developing Lateral Geniculate Nucleus and Medial Geniculate Nucleus Reveals Novel Roles for Zic4 and Foxp2 in Visual and Auditory Pathway Development

Abstract

Primary sensory nuclei of the thalamus process and relay parallel channels of sensory input into the cortex. The developmental processes by which these nuclei acquire distinct functional roles are not well understood. To identify novel groups of genes with a potential role in differentiating two adjacent sensory nuclei, we performed a microarray screen comparing perinatal gene expression in the principal auditory relay nucleus, the medial geniculate nucleus (MGN), and principal visual relay nucleus, the lateral geniculate nucleus (LGN). We discovered and confirmed groups of highly ranked, differentially expressed genes with qRT-PCR and in situ hybridization. A functional role for Zic4, a transcription factor highly enriched in the LGN, was investigated using Zic4-null mice, which were found to have changes in topographic patterning of retinogeniculate projections. Foxp2, a transcriptional repressor expressed strongly in the MGN, was found to be positively regulated by activity in the MGN. These findings identify roles for two differentially expressed genes, Zic4 and Foxp2, in visual and auditory pathway development. Finally, to test whether modality-specific patterns of gene expression are influenced by extrinsic patterns of input, we performed an additional microarray screen comparing the normal MGN to “rewired” MGN, in which normal auditory afferents are ablated and novel retinal inputs innervate the MGN. Data from this screen indicate that rewired MGN acquires some patterns of gene expression that are present in the developing LGN, including an upregulation of Zic4 expression, as well as novel patterns of expression which may represent unique processes of cross-modal plasticity.

What can mice tell us about Foxp2 function?

“…To date, work has concentrated mainly on the auditory system, presumably because of the importance of auditory processing for speech development. In mice, Foxp2 expression in the medial geniculate nucleus of the thalamus is dependent on auditory experience [40]. Foxp2-R552H heterozygotes (carrying the same mutation as the KE family) have auditory brainstem responses (ABRs) with longer latencies and smaller amplitudes than controls, which could reflect changes in the number or synchrony of activated neurons [41].…”

Ten-m2 Is Required for the Generation of Binocular Visual Circuits

“…While interactions with molecules that specify laterality are likely, an additional scenario is that multiple Ten-ms have complementary/combinatorial roles in shaping the ipsilateral projection. This could be facilitated via heterodimerization and/or heterophilic interactions (Feng et al, 2002;Hong et al, 2012;Mosca et al, 2012). For Ten-m2, overlap with regionally expressed molecules [e.g., ventral Vax2, temporal FoxD1, ventral Ten-m3, temporal Zic4 (Mui et al, 2002;Leamey et al, 2007;Horng et al, 2009;Carreres et al, 2011) could explain its graded requirement in specifying RGC fate.…”

“…This could be facilitated via heterodimerization and/or heterophilic interactions (Feng et al, 2002;Hong et al, 2012;Mosca et al, 2012). For Ten-m2, overlap with regionally expressed molecules [e.g., ventral Vax2, temporal FoxD1, ventral Ten-m3, temporal Zic4 (Mui et al, 2002;Leamey et al, 2007;Horng et al, 2009;Carreres et al, 2011) could explain its graded requirement in specifying RGC fate. Whether this occurs through direct binding with extracellular partners and/or signaling via its ICD, as well as the identity of the participants of such interactions, is of particular interest.…”

“…Whether the observed deficits are associated with changes to synaptic function and organization (Silva et al, 2011;Mosca et al, 2012) remains to be determined. Although Ten-m2 is expressed throughout the visual system, the largely normal contralateral responses argue that the impact of Ten-m2 deletion is highly localized, and on its own has a relatively limited impact on synaptic function.…”

Evo-devo, deep homology and FoxP2: implications for the evolution of speech and language

“…Foxp2 is strongly expressed after white noise stimulation of young mice [135]. Whether activity-driven FoxP2 expression plays a role in expression differences, such as the developmental downregulation in monkey striatum should be taken into account in future expression studies.…”