Ascl1 is a required downstream effector of Gsx gene function in the embryonic mouse telencephalon
© Wang et al.; licensee BioMed Central Ltd. 2009
Received: 28 October 2008
Accepted: 10 February 2009
Published: 10 February 2009
The homeobox gene Gsx2 (formerly Gsh2) is known to regulate patterning in the lateral ganglionic eminence (LGE) of the embryonic telencephalon. In its absence, the closely related gene Gsx1 (previously known as Gsh1) can partially compensate in the patterning and differentiation of ventral telencephalic structures, such as the striatum. However, the cellular and molecular mechanisms underlying this compensation remain unclear.
We show here that in the Gsx2 mutants Gsx1 is expressed in only a subset of the ventral telencephalic progenitors that normally express Gsx2. Based on the similarities in the expression of Gsx1 and Ascl1 (Mash1) within the Gsx2 mutant LGE, we examined whether Ascl1 plays an integral part in the Gsx1-based recovery. Ascl1 mutants show only modest alterations in striatal development; however, in Gsx2;Ascl1 double mutants, striatal development is severely affected, similar to that seen in the Gsx1;Gsx2 double mutants. This is despite the fact that Gsx1 is expressed, and even expands, in the Gsx2;Ascl1 mutant LGE, comparable to that seen in the Gsx2 mutant. Finally, Notch signaling has recently been suggested to be required for normal striatal development. In spite of the fact that Notch signaling is severely disrupted in Ascl1 mutants, it actually appears to be improved in the Gsx2;Ascl1 double mutants.
These results, therefore, reveal a non-proneural requirement of Ascl1 that together with Gsx1 compensates for the loss of Gsx2 in a subset of LGE progenitors.
The homeobox gene Gsx2 (formerly known as Gsh2) has been shown to be required for correct dorsal-ventral patterning in the embryonic mouse telencephalon [1–3]. Gsx2 accomplishes this by repressing dorsal telencephalic genes such as Pax6 and promoting the expression of ventral regulators such as Ascl1 (Mash1) and Dlx genes within ventricular zone (VZ) and subventricular zone (SVZ) progenitors of the lateral ganglionic eminence (LGE). Although Gsx2 mutants do not survive after birth , analyses at late embryonic stages have demonstrated severe reductions in markers of striatal projection neurons as well as olfactory bulb interneurons [1–3, 5, 6], both of which are derived from the LGE [7–10].
The closely related Gsx1 (Gsh1) is also expressed in the embryonic ventral telencephalon , although no telencephalic phenotype has been reported [5, 6]. Despite this, removal of Gsx1 on the Gsx2 mutant background eliminates nearly all striatal projection neurons and olfactory bulb interneurons, suggesting that Gsx1 can, at least in part, compensate for the loss of Gsx2 in the development of these ventral telencephalic structures. This compensation, however, is complex because Gsx1 is normally only present in the medial ganglionic eminence and the ventral-most portion of the LGE. In Gsx2 mutants, Gsx1 expression spreads dorsally to encompass the mutant LGE at mid-neurogenesis time points (for example, embryonic day (E)14), which is coincident with the re-establishment of ventral identity (for example, Ascl1 and Dlx expression) in the mutant LGE [5, 6]. Both Ascl1 and Dlx genes are known to be required for normal development of the striatum and olfactory bulb interneurons [12–16]. Moreover, a recent study  suggests that Ascl1 and Dlx genes control distinct and parallel pathways that act in the specification of olfactory bulb interneurons. The mechanism by which Gsx1 compensates for the loss of Gsx2 has not been fully elucidated. Moreover, the requirement for Ascl1 or Dlx genes in this process is unclear.
In this study we have examined the molecular mechanisms underlying Gsx1-mediated recovery of ventral telencephalic development in Gsx2 mutants. To do this, we have generated and analyzed Gsx2 EGFP mice as well as Gsx2;Ascl1 double mutants at multiple embryonic stages. Removal of Ascl1 from the Gsx2 mutant background results in a telencephalic phenotype nearly identical to the Gsx1:Gsx2 double mutant [5, 6]. These results thus indicate that Ascl1 is an essential component of the Gsx1-mediated recovery in a subset of LGE progenitors within the Gsx2 mutant telencephalon.
Gsx1 expression in the Gsx2 mutant telencephalon
Relationship between Gsx1 and Ascl1 in the Gsx2 mutant LGE
Ascl1 (Mash1) is known to be required for the normal development of the ventral telencephalon [14–16]. Furthermore, Ascl1 is dependent on Gsx2 for its normal expression in LGE progenitor cells [1–3], at least at early stages, before Gsx1 expression expands into the mutant LGE. Ascl1 is expressed by many cells within the Gsx2EGFP/+VZ, although they are mainly located at the VZ/SVZ boundary (Figure 2D, E). Interestingly, the pattern of Ascl1 expression in the Gsx2 mutants is very similar to that of Gsx1 (as revealed by Gsx1/2 staining; Figure 2G–J), with scattered cells in the VZ and the majority accumulated along the VZ/SVZ boundary. In Gsx1;Gsx2 double mutants, Ascl1 is not expressed in the LGE at early stages (for example, E12.5) but at later stages (for example, E15.5–16.5) it is found at low levels within the presumptive LGE region [5, 6]. This suggests that although Gsx proteins are not absolutely required for Ascl1 expression in the LGE, they are positive regulators of its expression. The overlap in Gsx1 and Ascl1 expression in the Gsx2 mutant LGE (Figure 2H, J) therefore suggests that Ascl1 may act in concert with Gsx1 for the compensation observed in Gsx2 mutants.
Expression of Gsx2 in the Ascl1 mutant
Gsx2;Ascl1 double mutants exhibit severe striatal defects
The striatum is composed of two anatomically and neurochemically distinct compartments termed the patch and matrix . The striatum-enriched phosphoprotein DARPP-32 has been shown to mark the forming patch compartment at perinatal time points  (Figure 4E). DARPP-32 is severely reduced in the Gsx2 mutant striatum (Figure 4F) [1, 2, 5, 24] while its expression was only moderately reduced in the Ascl1 mutants (Figure 4G). Interestingly, no DARPP-32-positive neurons were observed in the Gsx2;Ascl1 double mutant striatum (Figure 4H), a finding that is identical to that previously observed in the Gsx1;Gsx2 double mutant striatum . Calbindin is known to mark the matrix compartment in the mature striatum . As previously reported , calbindin expression is increased in the forming Gsx2 mutant striatum (Figure 4J) while a clear reduction in its expression was seen in the Ascl1 mutant striatum (Figure 4K). The rudimentary striatum present in the Gsx2;Ascl1 double mutant striatum did express calbindin (Figure 4L). Again, this was similar to that previously observed in the Gsx1;Gsx2 double mutant striatum . Thus, the similarities in the phenotypes observed in the Gsx2;Ascl1 and Gsx1;Gsx2 double mutants suggest that Ascl1 is required for the Gsx1-based striatal recovery in Gsx2 mutants.
Olfactory bulb defects in Gsx2;Ascl1 double mutants
Notch signaling in Gsx2;Ascl1 double mutants
The study of knock-out mice is essentially an investigation into the compensatory mechanisms (or lack thereof) when any given gene is inactivated. In the case of Gsx2, it has previously been shown that Gsx1 is involved in the partial recovery observed in these mutants [5, 6]. What remained unclear was why the Gsx1-dependent compensation was not more effective in restoring normal development. In addition to a delayed upregulation of Gsx1 in the Gsx2 mutant LGE [5, 6], we provide novel data here showing that Gsx1 is expressed only in a subset of LGE cells that would normally express Gsx2. Interestingly, these cells are largely located at the boundary between the VZ and SVZ, similar in location to that of Ascl1 expressing cells. Based on the facts that the striatal phenotype of the Gsx2;Ascl1 mutants is nearly identical to that observed in Gsx1;Gsx2 mutants [5, 6] and that Gsx1 expands in the Gsx2;Ascl1 mutants in a similar way to that observed in Gsx2 mutants, we conclude that Ascl1 is required downstream of Gsx1 for this recovery. These findings suggest that there are Ascl1-dependent and Ascl1-independent pathways for LGE development. This is in agreement with recent studies by Long et al. [17, 19] showing that Dlx1/2 and Ascl1 regulate parallel and overlapping pathways in LGE specification. Furthermore, our results indicate that the Ascl1-dependent pathway for LGE specification appears to be independent of its well-known role in regulating the Notch signaling pathway.
The mechanism by which Gsx1 is upregulated in the Gsx2 mutant LGE has been unclear. It does not appear that Gsx2 represses Gsx1 expression because only a subset of the cells that normally express Gsx2, particularly those at the VZ/SVZ boundary, are Gsx1-positive in the Gsx2 mutant LGE. It seems possible, therefore, that Gsx1 can only be expressed in certain cell types or in cells that have reached a particular level of maturation (that is, cells transitioning from the VZ to the SVZ). Indeed, it appears that Gsx1-positive cells in the medial ganglionic eminence region also reside largely in the VZ/SVZ boundary region (for example, Figure 2C). Interestingly, at early stages (that is, E12.5) in the Gsx2 mutants, the LGE SVZ does not form, and only after Gsx1 has expanded throughout the mutant LGE (that is, by E14–15) does the it do so in this mutant [2, 3, 5]. Together with the current findings, these results suggest that Gsx1 may be expressed in more mature progenitors and might even play a role in the maturation process.
Ascl1 has previously been implicated in the development of the striatum and olfactory bulb interneurons [14–17, 28]. In general, however, the requirement for Ascl1 in striatal and olfactory bulb development is not as great as that for Gsx2. In fact, the striatum of the Ascl1 mutant is only slightly reduced in size when compared to the wild type  (Figure 4). Moreover, the reduction in dopaminergic and GABAergic olfactory bulb interneurons  is not as severe as that observed in Gsx2 mutants [5, 6]. Although striatal development is only modestly affected by the loss of Ascl1, we show here that the added loss of Gsx2 results in a nearly complete loss of striatal development. This result is identical to that previously reported for Gsx1;Gsx2 double mutants [5, 6]. Thus, Ascl1 is absolutely essential for the Gsx1-mediated recovery observed in Gsx2 mutants. While Ascl1 appears to be downstream of Gsx2 [1–3], the relationship between Gsx1 and Ascl1 appears to be more complex. The loss of Gsx1 and Gsx2 severely depletes the expression of Ascl1 throughout embryogenesis [5, 6], suggesting that both are genetically upstream; however, our findings here also demonstrate a delay in the expression of Gsx1 in Gsx2;Ascl1 double mutants at early stages (for example, Figure 8D), potentially implicating Ascl1 in feedback regulation of Gsx1 expression.
Ascl1 is a known regulator of the Notch signaling pathway [14, 16] and Notch signaling has previously been implicated in controlling striatal development [16, 32]. It does not seem that the striatal defects observed in the Gsx2;Ascl1 double mutants, described here, are simply due to compound effects of the loss of Gsx2 and impaired Notch signaling because we observed an improvement in Notch signaling (as indicated by Hes5 and Dll1 expression) within LGE progenitors of the Gsx2;Ascl1 double mutants compared to Ascl1 mutants. Our interpretation of this result is that Gsx2;Ascl1 mutants are similar to Gsx2 mutants in that Ngn2 is allowed to expand ventrally into the LGE and, as a result, Notch signaling is improved. Clearly, Ascl1 plays a role in regulating Notch signaling within LGE progenitors [14, 16]; however, the fact that striatal development is not more severely affected in the Ascl1 mutant could suggest that Gsx2 normally works through another gene encoding a basic helix-loop-helix (bHLH) factor to regulate aspects of LGE neurogenesis.
A somewhat surprising finding that we observed in the Ascl1 mutants was that Gsx2 expression appeared to be increased at perinatal stages. This is not the case at early time points (for example, E12.5) and suggests that Ascl1 may play a role in depleting the Gsx2 progenitors during embryogenesis. The increased Gsx2 in the Ascl1 mutant LGE correlated well with the expression of Sp8, a zinc finger transcription factor that has previously been shown to be dependent on Gsx2 expression .
Previous studies have described a reduction in dopaminergic and GABAergic interneurons in the Ascl1 mutants [14, 28]; however, no data on other subtypes have been provided. We show here that unlike the dopaminergic and GABAergic subtypes, the CR interneurons are not reduced and may, in fact, be increased. The neurotransmitter of this subtype remains somewhat unclear. Recent reports suggests that as few as 14% are GABAergic , while others suggest that most if not all are GABAergic [30, 34]. Our data seem to support the former possibility (at least at this stage of development) since the reduction in GABAergic neurons (as marked by GAD67) is not paralleled by CR-positive cells in the Ascl1 mutant olfactory bulb. We have recently shown that the zinc finger transcription factor Sp8 is required for the normal development of the CR interneurons in the olfactory bulb . Accordingly, we found that in Ascl1 mutants at late stages of development, Sp8 staining is maintained in the dLGE and olfactory bulbs. Because Gsx2 is required for Sp8 expression in the dLGE and the latter is essential for normal CR interneuron production, it seems likely that the sequential expression of these two transcription factors cooperate to generate this interneuron subtype. However, despite that Gsx2 appears to function upstream of Ascl1, this bHLH factor does not actively promote CR interneuron development.
The origin of distinct subtypes of olfactory bulb interneurons has recently been the subject of considerable attention. Kohwi et al.  have recently suggested that CR interneurons arise from pallial and septal regions but not the dLGE. On the other hand, De Marchis et al.  found that these interneurons were generated from the postnatal region of the SVZ that directly derives from the dLGE. In support of this, Merkle et al.  showed that at least some CR neurons are derived from the rostral dorsal SVZ (a likely derivative of the dLGE). Although CR interneurons start to be produced at embryonic time points, a recent study by Batista-Brito et al.  have shown that most are generated at postnatal time points. Our data show that at least a few CR neurons are present in the late embryonic dLGE and that Ascl1 mutants appear to exhibit enhanced CR neuron production in the dLGE and possibly olfactory bulb. Thus, Ascl1 may play a role in the temporal regulation of CR interneuron production from the dLGE and its SVZ derivatives. In any case, our findings clearly demonstrate that the dLGE is a significant source of CR interneurons that are generated at embryonic time points; however, we cannot exclude the contribution of the septum in the generation of these interneurons as shown by Merkle et al. , particularly at early postnatal stages. Indeed, Gsx2 is expressed at high levels in both the dLGE as well as in the dorsal portion of the septum (Figure 2) and CR staining in the septal region is also lost in the Gsx2 mutant (Figure 7). Regardless of their origin, it seems that all subtypes of olfactory bulb interneurons, at least at embryonic time points, require Gsx2 for their normal production.
Our data show that Gsx1 compensates for the loss of Gsx2 gene function in only a subpopulation of the LGE progenitors that normally express Gsx2, which may explain why the compensation is not more complete. Additionally, we show that Ascl1 is an obligate factor for Gsx1 in the recovery process and that this is independent of its well-known proneural function.
Gsx2  and Ascl1  mice were genotyped as previously described [2, 14]. Interbreeding between Gsx2 and Ascl1 heterozygotes was performed to generate Ascl1;Gsx2 double heterozygotes, which were subsequently crossed to generate Ascl1;Gsx2 double homozygous mutants.
For staging of embryos, the morning of vaginal plug detection was designated as E0.5. At least three embryos of each genotype were examined for every stage studied and marker used. Embryos were fixed overnight in 4% paraformaldehyde at 4°C, rinsed extensively in phosphate-buffered saline and cryoprotected in 30% sucrose before sectioning at 12–14 μm on a cryostat. Sections were thaw-mounted onto SuperFrost®/Plus slides (Fisher Scientific, Pittsburgh, PA, USA) and stored at -20°C until used.
For immunohistochemistry, primary antibodies were used at the following concentrations: rabbit anti-Ascl1 (Mash1; 1:1,000; provided by J Johnson); rabbit anti-calbindin (1:2,500; provided by P Emson); goat anti-calretinin (1:2,000; Millipore, Billerica, MA, USA); rabbit anti-Dll (pan DLX; 1:400; provided by J Khotz); rabbit anti-FoxP1 (1:4,000; provided by E Morissey); rabbit anit-GAD67 (1:1,000; Millipore); goat anti-GFP (1:5,000; Abcam, Cambridge, MA, USA); rabbit anti-Gsx2 (1:5,000; ); rabbit anti-Gsx1/2 (1:2,000; provided by M Goulding); rabbit anti-Ki67 (1:1,000; Novocastra, Newcastle, UK); rabbit anti-Ngn2 (1:1,000; provided by M Nakafuku); rabbit anti-Sp8 (1:500; ). The secondary antibodies for brightfield staining were biotinylated swine anti-rabbit antibodies (1:200; DAKO, Glostrup, Denmark) and biotinylated horse anti-goat antibodies (1:200; Vector Laboratories, Burlingame, CA, USA). For visualization, the ABC kit (Vector Laboratories) followed by diaminobenzidine (DAB; Sigma, St. Louis, MO, USA) as the final chromogen were utilized. The secondary antibodies for fluorescent staining were donkey anti-goat antibodies conjugated to Cy2 (Jackson Immunoresearch, West Grove, PA, USA), and donkey anti-rabbit antibodies conjugated to Cy3 (Jackson Immunoresearch).
dorsal lateral ganglionic eminence
enhanced green fluorescent protein
glutamic acid decarboxylase (67 kDa)
lateral ganglionic eminence
We gratefully acknowledge the kind gifts of antibodies and probes from P Emson, M Goulding, J Johnson, J Kohtz, E Morrisey and M Nakafuku. This work was supported by the NIH grants NS044080 and MH069643 to KC and by the HFSPO grant RG160-2000B to FG and KC. RRW is supported by an NIH training grant (HD046387) and ZJA is supported by an NIH NRSA (DC008928).
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