The transcription factor Foxg1 regulates the competence of telencephalic cells to adopt subpallial fates in mice

Abstract

SUMMARYFoxg1 is required for development of the ventral telencephalon in the embryonic mammalian forebrain. Although one existing hypothesis suggests that failed ventral telencephalic development in the absence of Foxg1 is due to reduced production of the morphogens sonic hedgehog (Shh) and fibroblast growth factor 8 (Fgf8), the possibility that telencephalic cells lacking Foxg1 are intrinsically incompetent to generate the ventral telencephalon has remained untested. We examined the ability of Foxg1 -/-telencephalic cells to respond to Shh and Fgf8 by examining the expression of genes whose activation requires Shh or Fgf8 in vivo and by testing their responses to Shh and Fgf8 in culture. We found that many elements of the Shh and Fgf8 signalling pathways continue to function in the absence of Foxg1 but, nevertheless, we were unable to elicit normal responses of key ventral telencephalic marker genes in Foxg1 -/-telencephalic tissue following a range of in vivo and in vitro manipulations. We explored the development of Foxg1 -/-cells in Foxg1 -/-Foxg1 +/+ chimeric embryos that contained ventral telencephalon created by normally patterned wild-type cells. We found that Foxg1 -/-cells contributed to the chimeric ventral telencephalon, but that they retained abnormal specification, expressing dorsal rather than ventral telencephalic markers. These findings indicate that, in addition to regulating the production of ventralising signals, Foxg1 acts cell-autonomously in the telencephalon to ensure that cells develop the competence to adopt ventral identities. KEY WORDS: Foxg1, Telencephalon, Patterning, MouseThe transcription factor Foxg1 regulates the competence of telencephalic cells to adopt subpallial fates in mice -/-cells contributed to the chimeric ventral telencephalon, but the mutant cells were specified abnormally, expressing dorsal rather than ventral telencephalic markers. These findings indicate that, in addition to regulating production of ventralising cues, Foxg1 has a crucial cell-autonomous function, giving telencephalic cells the competence to adopt ventral identities. MATERIALS AND METHODS Animals Foxg1-/-embryos were generated by intercrossing Foxg1 +/-mice Production of chimeric animalsChimeras were produced by morula aggregation. +/+ embryos for aggregation were from (BALB/c ϫ A/J) F 2 intercrosses. Embryos were collected from superovulated females and aggregated (West and Flockhart, 1994). The two morulae for aggregation differed at the Gpi1 locus (encoding glucose phosphate isomerase). Aggregated embryos were cultured overnight, transferred to recipient pseudopregnant females and recovered at embryonic day 12.5 (E12.5). The genotype of each chimera was determined by PCR . The use of two null-mutant Foxg1 alleles allowed distinction between chimeras containing Foxg1 lacZ/Cre (Foxg1 -/-) compound heterozygous cells and those containing heterozygous (Foxg1 lacZ/+ or Foxg1 +/Cre ) or wild-type (Foxg1 +/+ ) cells. The global contribution of each morula to the chimera was estimated using Gpi1 elect...

FoxG1 and TLE2 act cooperatively to regulate ventral telencephalon formation

“…Nkx2.1 is also expressed in the diencephalon, but within the telencephalon it is good marker for the ventral-most part of the subpallium: the pallidum or medial ganglionic eminence (Bachy et al, 2002). In FoxG1 MO-injected embryos, the subpallial expression of Nkx2.1 was entirely missing (100%, n11), consistent with previous data from mouse and fish (Martynoga et al, 2005;Manuel et al, 2010;Danesin et al, 2009), and in TLE2 MO embryos it was greatly reduced (70%, n10) (Fig. 7G).…”

“…Here, we suggest that this event is mediated by the specific interaction of FoxG1 with the transcriptional co-repressor TLE2, which might provide a mechanism for the cell-autonomous role of FoxG1 in this region (Manuel et al, 2010). Although we have focused on TLE2, we cannot exclude a contribution by TLE1 and finer assays will be needed to distinguish the contribution of each factor.…”

“…In fish, morpholino (MO) knockdown experiments demonstrated a similar loss of the subpallium, accompanied by a ventral expansion of dorsal telencephalon markers and a 'slippage' of ventral telencephalic cells into the hypothalamic territory of the diencephalon (Danesin et al, 2009). Recently, it has been shown that Foxg1 is required cellautonomously in the acquisition of ventral (subpallial) telencephalic identity in the mouse (Manuel et al, 2010).…”

MicroRNA-9 Regulates Neurogenesis in Mouse Telencephalon by Targeting Multiple Transcription Factors

“…9T ). Foxg1 is also expressed in subpallium, but its role in subpallial progenitor proliferation and differentiation has been unclear in Foxg1 mutants because of the earlier defect in the subpallial specification (Martynoga et al, 2005;Manuel et al, 2010). Foxg1 protein expression was modest in the E15.5 wildtype subpallium but enhanced in the miR-9-2/3 double-mutant subpallium (Fig.…”

Altered expression of neuropeptides in FoxG1-null heterozygous mutant mice

“…9 It is one of the first transcription factors activated during telencephalic development, acting as an integrator of signaling centers. [10][11][12] Its role has been extensively characterized in mice demonstrating that it is implicated in regulating cortical arealization, expansion of the cortical progenitor pool and regulation of progenitor cell cycle length. [13][14][15][16][17][18] In particular, the protein acts by maintaining telencephalic progenitor status and ensuring that these progenitors maintain appropriate cell cycle kinetics.…”