Altered Molecular Regionalization and Normal Thalamocortical Connections in Cortex-SpecificPax6Knock-Out Mice

Abstract

Transcription factor Pax6 exerts a prominent rostrolateral high to caudomedial low expression gradient in the cortical progenitors and have been implicated in regulation of area identity in the mammalian cortex. Herein, we analyzed the role of Pax6 in molecular arealization and development of thalamocortical connections in the juvenile cortex-specific conditional Pax6 knock-out mice (Pax6cKO). Using a set of molecular markers of positional identity (Id2, Cadherin6, COUP-TF1, RZR␤, and EphA7), we show that, in the juvenile Pax6cKO, the relative size of caudal cortical areas (putative visual and somatosensory) are mildly enlarged, whereas the rostral domain (putative motor) is severely reduced. Despite the rostral shift of graded expression of areal markers, the distribution of area-specific thalamocortical and corticofugal projections appear normal in the Pax6cKO. This indicates that change of the size of cortical areas is not accompanied by a change in cortical identity. We show furthermore that, despite a severe depletion of supragranular cortical layers and accumulation of cells along the pallial-subpallial boundary, thalamocortical fibers establish a periphery-related pattern of the somatosensory cortex in normal position in Pax6cKO. Our findings indicate that Pax6 expression gradients in cortical progenitors do not directly impart thalamocortical or corticofugal areal identity.

Selective Cortical Layering Abnormalities and Behavioral Deficits in Cortex-Specific Pax6 Knock-Out Mice

“…In this line of evidence, previous data indicated that overexpression of Pax6 in vivo affected the RG proliferation and caused progenitor apoptosis only during early neurogenesis (Berger et al, 2007). Notably, the expansion of IGLs and the reduction of SGL neuronal sets observed in Emx1-Cre/Pax6cKO mice was predominant in the rostral cortex, which correlates with a severe diminishing of the motor area size in these mutants (Piñon et al, 2008). We propose, therefore, that Pax6 deficiency, with failure in progenitor cell cycle progression at the onset of cortical neurogenesis, causes both laminar and area disturbances of the mature rostral cortex.…”

“…Defects in differentiation of late-prenatal and postnatal RG progenitors in Emx1-Cre/Pax6cKO mutant The brain of the juvenile (P10) Emx1-Cre/Pax6cKO mouse contains dense cell masses at the PSPB (Piñon et al, 2008). These large cell protrusions were strongly labeled by the subpallial markers, Dlx1 (Fig.…”

“…Previous data indicated that, in the absence of Pax6, the MZ of the Sey/Sey embryonic cortex contains an increased number of Reelinϩ/Calretininϩ neurons, which possibly originate from the remnant vesicles of the missing olfactory bulbs (OBs) (Stoykova et al, 2003). To determine whether the expression of Pax6 in cortical progenitors could intrinsically influence the generation of MZ neurons, we analyzed the MZ in cortex-specific conditional Pax6 mutant (Pax6 fl/fl ; Emx1-Cre) (Piñon et al, 2008) (designated thereafter Emx1-Cre/ Pax6cKO), which have normally developed olfactory bulbs (Piñon et al, 2008). Quantitative analysis of the Reelin-, Calretinin-, and Tbr1-expressing cells was conducted by immunolabeling at E15.5, because Reelin expression diminishes after birth.…”

“…The expression gradient of Pax6 in the cortical ventricular zone (VZ) (Stoykova et al, 1997) suggests that Pax6 might confer rostral cortical area identities (O'Leary and Nakagawa, 2002). However, although molecular markers for caudal domains are expanded into rostral cortex in the absence of Pax6 function (Bishop et al, 2000;Piñon et al, 2008), the main cortical functional domains show normal thalamocortical connectivity, suggesting that the graded expression of Pax6 in RGPs does not impact intrinsic area identity (Piñon et al, 2008).…”

Gradients in the Brain: The Control of the Development of Form and Function in the Cerebral Cortex

“…Of these transcription factors, evidence supports a patterning role for Sp8 and Emx2, whereas the effects of Pax6 on area patterning have been recently suggested by both gain-and lossof-function studies to be indirect (Fig. 3B) (Manuel et al 2007;Pinon et al 2008).…”