Telencephalic Patterning Research Articles

Patterns of early embryogenesis and growth in the olfactory system of chick (Gallus gallus domesticus) based on iodine-enhanced micro-computed tomography.

The vertebrate olfactory system entails a complex set of neural/support structures that bridge morphogenetic regions. The developmental mechanisms coordinating this bridge remain unclear, even for model organisms such as chick, Gallus gallus. Here, we combine previous growth data on the chick olfactory apparatus with new samples targeting its early embryogenesis. The purpose is to illuminate how early developmental dynamics integrate with scaling relationships to produce adult form and, potentially, evolutionary patterns. Olfactory structures, including epithelium, turbinate, nerve, and olfactory bulb, are considered in the context of neighboring nasal and brain structures. Axonal outgrowth from the olfactory epithelium, which eventually connects receptor neurons with the brain, begins earlier than previously established. This dynamic marks the beginning of a complex pattern of early differential growth wherein the olfactory bulbs scale with positive allometry relative to both brain volume and turbinate area, which in turn scale isometrically with one another. The mechanisms driving observed patterns of organogenesis and growth remain unclear awaiting experimental evidence. We discuss competing hypotheses, including the possibility that broad-based isometry of olfactory components reflects constraints imposed by high levels of functional/structural integration. Such integration would include the frontonasal prominence having a strong influence on telencephalic patterning.

Co-expression of prepulse inhibition and Schizophrenia genes in the mouse and human brain

Schizophrenia is a complex psychiatric disorder with genetic and phenotypic heterogeneity. Accumulating rare and genome-wide association study (GWAS) common risk variant information has yet to yield robust mechanistic insight. Leveraging large-scale gene deletion mouse phenomic data thus has potential to functionally interrogate and prioritize human disease genes. To this end, we applied a cross-species network-based approach to parse an extensive mouse gene set (188 genes) associated with disrupted prepulse inhibition (PPI), a Schizophrenia endophenotype. Integrating PPI genes with high-resolution mouse and human brain transcriptomic data, we identified functional and disease coherent co-expression modules through hierarchical clustering and weighted gene co-expression network analysis (WGCNA). In two modules, Schizophrenia risk and mouse PPI genes converged based on telencephalic patterning. The associated neuronal genes were highly expressed in cingulate cortex and hippocampus; implicated in synaptic function and neurotransmission and overlapped with the greatest proportion of rare variants. Concordant neuroanatomical patterning revealed novel core Schizophrenia-relevant genes consistent with the Omnigenic hypothesis of complex traits. Among other genes discussed, the developmental and post-synaptic scaffold TANC2 (Tetratricopeptide repeat, ankyrin repeat and coiled-coil containing 2) emerged from both networks as a novel core genetic driver of Schizophrenia altering PPI. Aspects of psychiatric disease comorbidity and phenotypic heterogeneity are also explored. Overall, this study provides a framework and galvanizes the value of mouse preclinical genetics and PPI to prioritize both existing and novel human Schizophrenia candidate genes as druggable targets.

Foxg1 Directly Represses Dbx1 to Confine the POA and Subsequently Regulate Ventral Telencephalic Patterning.

During early development, signaling centers, such as the cortical hem and the preoptic area (POA), are critical for telencephalic patterning. However, the mechanisms underlying the maintenance of signal centers are poorly understood. Here, we report that the transcription factor Foxg1 is required to confine the POA, a resource of Sonic Hedgehog (Shh) that is pivotal for ventral telencephalic development. Cell-specific deletion of Foxg1 achieved by crossing Foxg1fl/fl with Dbx1-cre or Nestin-CreER combined with tamoxifen induction results in a dramatic expansion of the POA accompanied by the significantly increased activity of the Shh signaling pathway. Ventral pattern formation was severely impaired. Moreover, we demonstrated that Foxg1 directly represses Dbx1 to restrict the POA. Furthermore, we found that the ventral pallium was expanded, which might also contribute to the observed patterning defects. These findings will improve our understanding of the maintenance of signal centers and help to elucidate the mechanisms underlying ventral telencephalic patterning.

FoxG1 Directly Represses Dentate Granule Cell Fate During Forebrain Development.

The cortex consists of 100s of neuronal subtypes that are organized into distinct functional regions; however, the mechanisms underlying cell fate determination remain unclear. Foxg1 is involved in several developmental processes, including telencephalic patterning, cell proliferation and cell fate determination. Constitutive disruption of Foxg1 leads to the transformation of cortical neurons into Cajal-Retzius (CR) cells, accompanied by a substantial expansion of the cortical hem through the consumption of the cortex. However, rather than the induction of a cell fate switch, another group has reported a large lateral to medial repatterning of the developing telencephalon as the explanation for this change in cell type output. Here, we conditionally disrupted Foxg1 in telencephalic progenitor cells by crossing Foxg1fl/fl mice with Nestin-CreERTM mice combined with tamoxifen (TM) induction at distinct developmental stages beginning at E10.5 to further elucidate the role of FoxG1 in cell fate determination after telencephalon pattern formation. The number of dentate gyrus (DG) granule-like cells was significantly increased in the cortex. The increase was even detected after deletion at E14.5. In vivo mosaic deletion and in vitro cell culture further revealed a cell-autonomous role for FoxG1 in repressing granule cell fate. However, the cortical hem, which is required for the patterning and the development of the hippocampus, was only slightly enlarged and thus may not contribute to the cell fate switch. Lef1 expression was significantly upregulated in the lateral, cortical VZ and FoxG1 may function upstream of Wnt signaling. Our results provide new insights into the functions of FoxG1 and the mechanisms of cell fate determination during telencephalic development.

Sonic Hedgehog Signaling Rises to the Surface: Emerging Roles in Neocortical Development.

The mammalian neocortex is composed of a diverse population of neuronal and glial cells that are crucial for cognition and consciousness. Orchestration of molecular events that lead to the production of distinct cell lineages is now a major research focus. Recent studies in mammalian animal models reveal that Sonic Hedgehog (Shh) signaling plays crucial roles in this process. In this review, we will evaluate these studies and provide insights on how Shh signaling specifically influence cortical development, beyond its established roles in telencephalic patterning, by specifically focusing on its impact on cells derived from the cortical radial glial (RG) cells. We will also assess how these findings further advance our knowledge of neurological diseases and discuss potential roles of targeting Shh signaling in therapies.

Sfrp1 Modulates Cell-signaling Events Underlying Telencephalic Patterning, Growth and Differentiation.

The mammalian dorsal telencephalic neuroepithelium develops-from medial to lateral-into the choroid plaque, cortical hem, hippocampal primordium and isocortex under the influence of Bmp, Wnt and Notch signaling. Correct telencephalic development requires a tight coordination of the extent/duration of these signals, but the identification of possible molecular coordinators is still limited. Here, we postulated that Secreted Frizzled Related Protein 1 (Sfrp1), a multifunctional regulator of Bmp, Wnt and Notch signaling strongly expressed during early telencephalic development, may represent 1 of such molecules. We report that in E10.5-E12.5 Sfrp1-/- embryos, the hem and hippocampal domains are reduced in size whereas the prospective neocortex is medially extended. These changes are associated with a significant reduction of the medio-lateral telencephalic expression of Axin2, a read-out of Wnt/βcatenin signaling activation. Furthermore, in the absence of Sfrp1, Notch signaling is increased, cortical progenitor cell cycle is shorter, with expanded progenitor pools and enhanced generation of early-born neurons. Hence, in postnatal Sfrp1-/- animals the anterior hippocampus is reduced and the neocortex is shorter in the antero-posterior and medio-lateral axis but is thicker. We propose that, by controlling Wnt and Notch signaling in opposite directions, Sfrp1 promotes hippocampal patterning and balances medio-lateral and antero-posterior cortex expansion.

Plag1 and Plagl2 have overlapping and distinct functions in telencephalic development.

ABSTRACTThe Plag gene family has three members; Plagl1/Zac1, which is a tumor suppressor gene, and Plag1 and Plagl2, which are proto-oncogenes. All three genes are known to be expressed in embryonic neural progenitors, and Zac1 regulates proliferation, neuronal differentiation and migration in the developing neocortex. Here we examined the functions of Plag1 and Plagl2 in neocortical development. We first attempted, and were unable to generate, E12.5 Plag1;Plagl2 double mutants, indicating that at least one Plag1 or Plagl2 gene copy is required for embryonic survival. We therefore focused on single mutants, revealing a telencephalic patterning defect in E12.5 Plagl2 mutants and a proliferation/differentiation defect in Plag1 mutant neocortices. Specifically, the ventral pallium, a dorsal telencephalic territory, expands into the ventral telencephalon in Plagl2 mutants. In contrast, Plag1 mutants develop normal regional territories, but neocortical progenitors proliferate less and instead produce more neurons. Finally, in gain-of-function studies, both Plag1 and Plagl2 reduce neurogenesis and increase BrdU-uptake, indicative of enhanced proliferation, but while Plagl2 effects on proliferation are more immediate, Plag1 effects are delayed. Taken together, we found that the Plag proto-oncogenes genes are essential regulators of neocortical development and although Plag1 and Plagl2 functions are similar, they do not entirely overlap. This article has an associated First Person interview with the first author of the paper.

Direct Interactions BetweenGli3,Wnt8b, andFgfsUnderlie Patterning of the Dorsal Telencephalon

A key step in the development of the cerebral cortex is a patterning process, which subdivides the telencephalon into several molecularly distinct domains and is critical for cortical arealization. This process is dependent on a complex network of interactions between signaling molecules of the Fgf and Wnt gene families and the Gli3 transcription factor gene, but a better knowledge of the molecular basis of the interplay between these factors is required to gain a deeper understanding of the genetic circuitry underlying telencephalic patterning. Using DNA-binding and reporter gene assays, we here investigate the possibility that Gli3 and these signaling molecules interact by directly regulating each other's expression. We show that Fgf signaling is required for Wnt8b enhancer activity in the cortical hem, whereas Wnt/β-catenin signaling represses Fgf17 forebrain enhancer activity. In contrast, Fgf and Wnt/β-catenin signaling cooperate to regulate Gli3 expression. Taken together, these findings indicate that mutual interactions between Gli3, Wnt8b, and Fgf17 are crucial elements of the balance between these factors thereby conferring robustness to the patterning process. Hence, our study provides a framework for understanding the genetic circuitry underlying telencephalic patterning and how defects in this process can affect the formation of cortical areas.

Conversion of monkey fibroblasts to transplantable telencephalic neuroepithelial stem cells

Non-human primates provide optimal models for the development of stem cell therapies. Although somatic cells have been converted into neural stem/progenitor cells, it is unclear whether telencephalic neuroepithelial stem cells (NESCs) with stable properties can be generated from fibroblasts in primate. Here we report that a combination of transcription factors (Oct4, Sox2, Klf4) with a new culture medium induces rhesus monkey fibroblasts into NESCs, which can develop into miniature neural tube (NT)-like structures at a cell level. Furthermore, single induced NESCs (iNESCs) can generate later-stage 3D-NTs after grown on matrigel in suspension culture. iNESCs express NT cell markers, have a unique gene expression pattern biasing towards telencephalic patterning, and give rise to cortical neurons. Via transplantation, single iNESCs can extensively survive, regenerate myelinated neuron axons and synapse structures in adult monkey striatum and cortex, and differentiate into cortical neurons. Successful transplantation is closely associated with graft regions and grafted cell identities. The ability to generate defined and transplantable iNESCs from primate fibroblasts under a defined condition with predictable fate choices will facilitate disease modeling and cell therapy.

Sox2 is required for embryonic development of the ventral telencephalon through the activation of the ventral determinants Nkx2.1 and Shh

The Sox2 transcription factor is active in stem/progenitor cells throughout the developing vertebrate central nervous system. However, its conditional deletion at E12.5 in mouse causes few brain developmental problems, with the exception of the postnatal loss of the hippocampal radial glia stem cells and the dentate gyrus. We deleted Sox2 at E9.5 in the telencephalon, using a Bf1-Cre transgene. We observed embryonic brain defects that were particularly severe in the ventral, as opposed to the dorsal, telencephalon. Important tissue loss, including the medial ganglionic eminence (MGE), was detected at E12.5, causing the subsequent impairment of MGE-derived neurons. The defect was preceded by loss of expression of the essential ventral determinants Nkx2.1 and Shh, and accompanied by ventral spread of dorsal markers. This phenotype is reminiscent of that of mice mutant for the transcription factor Nkx2.1 or for the Shh receptor Smo. Nkx2.1 is known to mediate the initial activation of ventral telencephalic Shh expression. A partial rescue of the normal phenotype at E14.5 was obtained by administration of a Shh agonist. Experiments in Medaka fish indicate that expression of Nkx2.1 is regulated by Sox2 in this species also. We propose that Sox2 contributes to Nkx2.1 expression in early mouse development, thus participating in the region-specific activation of Shh, thereby mediating ventral telencephalic patterning induction.

Gli3 Controls Corpus Callosum Formation by Positioning Midline Guideposts During Telencephalic Patterning

The corpus callosum (CC) represents the major forebrain commissure connecting the 2 cerebral hemispheres. Midline crossing of callosal axons is controlled by several glial and neuronal guideposts specifically located along the callosal path, but it remains unknown how these cells acquire their position. Here, we show that the Gli3 hypomorphic mouse mutant Polydactyly Nagoya (Pdn) displays agenesis of the CC and mislocation of the glial and neuronal guidepost cells. Using transplantation experiments, we demonstrate that agenesis of the CC is primarily caused by midline defects. These defects originate during telencephalic patterning and involve an up-regulation of Slit2 expression and altered Fgf and Wnt/β-catenin signaling. Mutations in sprouty1/2 which mimic the changes in these signaling pathways cause a disorganization of midline guideposts and CC agenesis. Moreover, a partial recovery of midline abnormalities in Pdn/Pdn;Slit2(-/-) embryos mutants confirms the functional importance of correct Slit2 expression levels for callosal development. Hence, Gli3 controlled restriction of Fgf and Wnt/β-catenin signaling and of Slit2 expression is crucial for positioning midline guideposts and callosal development.

The Doublesex Homolog Dmrt5 is Required for the Development of the Caudomedial Cerebral Cortex in Mammals

Regional patterning of the cerebral cortex is initiated by morphogens secreted by patterning centers that establish graded expression of transcription factors within cortical progenitors. Here, we show that Dmrt5 is expressed in cortical progenitors in a high-caudomedial to low-rostrolateral gradient. In its absence, the cortex is strongly reduced and exhibits severe abnormalities, including agenesis of the hippocampus and choroid plexus and defects in commissural and thalamocortical tracts. Loss of Dmrt5 results in decreased Wnt and Bmp in one of the major telencephalic patterning centers, the dorsomedial telencephalon, and in a reduction of Cajal-Retzius cells. Expression of the dorsal midline signaling center-dependent transcription factors is downregulated, including Emx2, which promotes caudomedial fates, while the rostral determinant Pax6, which is inhibited by midline signals, is upregulated. Consistently, Dmrt5(-/-) brains exhibit patterning defects with a dramatic reduction of the caudomedial cortex. Dmrt5 is increased upon the activation of Wnt signaling and downregulated in Gli3(xt/xt) mutants. We conclude that Dmrt5 is a novel Wnt-dependent transcription factor required for early cortical development and that it may regulate initial cortical patterning by promoting dorsal midline signaling center formation and thereby helping to establish the graded expression of the other transcription regulators of cortical identity.

Wnt/β‐catenin signaling is disrupted in theextra‐toes(Gli3Xt/Xt) mutant from early stages of forebrain development, concomitant with anterior neural plate patterning defects

The zinc finger transcription factor Gli3 is essential for normal development of the forebrain. Mutant mice with no functional Gli3 (extra-toes, Gli3(Xt/Xt) mutants) display a massive reduction in the size of the telencephalic lobes and absence of dorsomedial telencephalic structures, including the cortical hem, which normally expresses a number of Wnt molecules essential for patterning the hippocampus. Dorsomedial telencephalic Wnt activity, transduced through the Wnt/β-catenin signaling pathway, is also required for hippocampal specification and dorsoventral telencephalic patterning. Wnts whose normal expression is restricted to the cortical hem are completely absent in Gli3(Xt/Xt) embryos, but some expression of those Wnts with a broader expression domain persists, raising the possibility that Wnt/β-catenin signaling may still be active in this mutant. We examined whether the Wnt expression that persists in the Gli3(Xt/Xt) mutant neocortex activates Wnt/β-catenin signaling, using the BAT-gal transgenic reporter. We found Wnt/β-catenin signaling consistently decreased in the forebrains of Gli3(Xt/Xt) mutants, even prior to the formation of the cortical hem. This is accompanied by a severe reduction in expression of Wnt7b and Wnt8b at the lateral edges of the anterior neural plate that will give rise to the pallium. In addition, we found a significant increase in the expression of rostroventral markers of the anterior neural plate that will give rise to the basal forebrain. Our data reveal that Gli3 is required at the neural plate stage to regulate Wnt expression and Wnt/β-catenin signaling in the presumptive forebrain and confirm its previously proposed role in patterning the anterior neural plate.

Primary cilia control telencephalic patterning and morphogenesis via Gli3 proteolytic processing

Primary cilia have essential functions in vertebrate development and signaling. However, little is known about cilia function in brain morphogenesis, a process that is severely affected in human ciliopathies. Here, we study telencephalic morphogenesis in a mouse mutant for the ciliopathy gene Ftm (Rpgrip1l). We show that the olfactory bulbs are present in an ectopic location in the telencephalon of Ftm(-/-) fetuses and do not display morphological outgrowth at the end of gestation. Investigating the developmental origin of this defect, we have established that E12.5 Ftm(-/-) telencephalic neuroepithelial cells lack primary cilia. Moreover, in the anterior telencephalon, the subpallium is expanded at the expense of the pallium, a phenotype reminiscent of Gli3 mutants. This phenotype indeed correlates with a decreased production of the short form of the Gli3 protein. Introduction of a Gli3 mutant allele encoding the short form of Gli3 into Ftm mutants rescues both telencephalic patterning and olfactory bulb morphogenesis, despite the persistence of cilia defects. Together, our results show that olfactory bulb morphogenesis depends on primary cilia and that the essential role of cilia in this process is to produce processed Gli3R required for developmental patterning. Our analysis thus provides the first in vivo demonstration that primary cilia control a developmental process via production of the short, repressor form of Gli3. Moreover, our findings shed light on the developmental origin of olfactory bulb agenesis and of other brain morphogenetic defects found in human diseases affecting the primary cilium.

TheGli3Hypomorphic MutationPdnCauses Selective Impairment in the Growth, Patterning, and Axon Guidance Capability of the Lateral Ganglionic Eminence

Previous studies have defined a requirement for Sonic hedgehog (Shh) signaling in patterning the ventral telencephalon, a major source of the neuronal diversity found in the mature telencephalon. The zinc finger transcription factor Gli3 is a critical component of the Shh signaling pathway and its loss causes major defects in telencephalic development. Gli3 is expressed in a graded manner along the dorsoventral axis of the telencephalon but it is unknown whether Gli3 expression levels are important for dorsoventral telencephalic patterning. To address this, we used the Gli3 hypomorphic mouse mutant Polydactyly Nagoya (Pdn). We show that in Pdn/Pdn embryos, the telencephalic expression of Gli3 remains graded, but Gli3 mRNA and protein levels are reduced, resulting in an upregulation of Shh expression and signaling. These changes mainly affect the development of the lateral ganglionic eminence (LGE), with some disorganization of the medial ganglionic eminence mantle zone. The pallial/subpallial boundary is shifted dorsally and the production of postmitotic neurons is reduced. Moreover, LGE pioneer neurons that guide corticofugal axons into the LGE do not form properly, delaying the entry of corticofugal axons into the ventral telencephalon. Pdn/Pdn mutants also show severe pathfinding defects of thalamocortical axons in the ventral telencephalon. Transplantation experiments demonstrate that the intrinsic ability of the Pdn ventral telencephalon to guide thalamocortical axons is compromised. We conclude that correct Gli3 levels are particularly important for the LGE's growth, patterning, and development of axon guidance capabilities.

Role of Fgf8 signalling in the specification of rostral Cajal-Retzius cells.

Cajal-Retzius (CR) cells play a key role in the formation of the cerebral cortex. These pioneer neurons are distributed throughout the cortical marginal zone in distinct graded distributions. Fate mapping and cell lineage tracing studies have recently shown that CR cells arise from restricted domains of the pallial ventricular zone, which are associated with signalling centres involved in the early regionalisation of the telencephalic vesicles. In this study, we identified a subpopulation of CR cells in the rostral telencephalon that expresses Er81, a downstream target of Fgf8 signalling. We investigated the role of the rostral telencephalic patterning centre, which secretes FGF molecules, in the specification of these cells. Using pharmacological inhibitors and genetic inactivation of Fgf8, we showed that production of Fgf8 by the rostral telencephalic signalling centre is required for the specification of the Er81+ CR cell population. Moreover, the analysis of Fgf8 gain-of-function in cultivated mouse embryos and of Emx2 and Gli3 mutant embryos revealed that ectopic Fgf8 signalling promotes the generation of CR cells with a rostral phenotype from the dorsal pallium. These data showed that Fgf8 signalling is both required and sufficient to induce rostral CR cells. Together, our results shed light on the mechanisms specifying rostral CR cells and further emphasise the crucial role of telencephalic signalling centres in the generation of distinct CR cell populations.

MAP'ing CNS Development and Cognition: An ERKsome Process

The ERK MAP kinase signaling cascade plays critical roles in brain development, learning, memory, and cognition. It has recently been appreciated that mutation or deletion of elements within this signaling pathway leads to developmental syndromes in humans that are associated with impaired cognitive function and autism. Here, we review recent studies that provide insight into the biological roles of the ERKs in the brain that may underlie the cognitive deficits seen in these syndromes.

Patterning the Dorsal Telencephalon: A Role for Sonic Hedgehog?

Division of the telencephalic vesicle into hemispheres and specification of the cerebral cortex are key stages in forebrain development. We investigate the interplay in these processes of Sonic hedgehog (Shh), fibroblast growth factors (Fgfs), and the transcription factor Gli3, which in its repressor form (Gli3R) antagonizes Shh signaling and downregulates expression of several Fgf genes. Contrary to previous reports, Shh is not required for dorsal hemisphere separation. Mice lacking Shh develop a dorsal telencephalic midline, a cortical hem, and two cortical hemispheres. The hemispheres do not divide rostrally, probably because of reduced local Fgf gene expression, resulting from the loss of Shh inhibition of Gli3R. Removing one functional copy of Gli3 substantially rescues Fgf expression and rostral telencephalic morphology. In mice lacking Gli3 function, cortical development is arrested, and ventral gene expression invades the dorsal telencephalon. These defects are potentially explained by disinhibition of Shh activity. However, when both copies of Shh are removed from Gli3-null mice, dorsal telencephalic defects persist. One such defect is a large dorsal expansion of the expression of Fgf genes. Fgf15 expression, for example, expands from a discrete ventral domain throughout the dorsal telencephalon. We propose that Fgf signaling, known to ventralize the telencephalon in a Shh-independent manner, suppresses cortical fate in the absence of Gli3. Our findings point away from Shh involvement in dorsal telencephalic patterning and encourage additional exploration of Fgf signaling and Gli3 repression in corticogenesis.

Region-specific requirement for cholesterol modification of sonic hedgehog in patterning the telencephalon and spinal cord

Sonic hedgehog (Shh) secreted from the axial signaling centers of the notochord and prechordal plate functions as a morphogen in dorsoventral patterning of the neural tube. Active Shh is uniquely cholesterol-modified and the hydrophobic nature of cholesterol suggests that it might regulate Shh spreading in the neural tube. Here, we examined the capacity of Shh lacking the cholesterol moiety (ShhN) to pattern different cell types in the telencephalon and spinal cord. In mice expressing ShhN, we detected low-level ShhN in the prechordal plate and notochord, consistent with the notion that ShhN can rapidly spread from its site of synthesis. Surprisingly, we found that low-level ShhN can elicit the generation of a full spectrum of ventral cell types in the spinal cord, whereas ventral neuronal specification and ganglionic eminence development in the Shh(N/-) telencephalon were severely impaired, suggesting that telencephalic patterning is more sensitive to alterations in local Shh concentration and spreading. In agreement, we observed induction of Shh pathway activity and expression of ventral markers at ectopic sites in the dorsal telencephalon indicative of long-range ShhN activity. Our findings indicate an essential role for the cholesterol moiety in restricting Shh dilution and deregulated spread for patterning the telencephalon. We propose that the differential effect of ShhN in patterning the spinal cord versus telencephalon may be attributed to regional differences in the maintenance of Shh expression in the ventral neuroepithelium and differences in dorsal tissue responsiveness to deregulated Shh spreading behavior.

Sp8 exhibits reciprocal induction with Fgf8 but has an opposing effect on anterior-posterior cortical area patterning

Telencephalic patterning centers, defined by the discrete expression domains of distinct morphogens, Fgfs in the commissural plate (CoP), Wnts and Bmps in the cortical hem, and a ventral domain of Sonic hedgehog (Shh), are postulated to establish during development the initial patterning of the telencepahlon, including the neocortex. We show that the expression patterns of Sp5, Sp8, and Sp9, members of the Sp8-like family that are homologues of Drosophila buttonhead, correlate during early embryonic development with these three telencephalic patterning centers. To study potential functional relationships, we focused on Sp8, because it is transiently expressed in the CoP coincident with the expression of Fgf8, a morphogen implicated in area patterning of the neocortex. We also show that Sp8 is expressed in cortical progenitors in a high to low anterior-medial to posterior-lateral gradient across the ventricular zone. We used in utero electroporation of full-length and chimeric expression constructs to perform gain-of-function and loss-of-function studies of interactions between Sp8 and Fgf8 and their roles in cortical area patterning. We show that Fgf8 and Sp8 exhibit reciprocal induction in vivo in the embryonic telencephalon. Sp8 also induces downstream targets of Fgf8, including ETS transcription factors. In vitro assays show that Sp8 binds Fgf8 regulatory elements and is a direct transcriptional activator of Fgf8. We also show that Sp8 induction of Fgf8 is repressed by Emx2 in vitro, suggesting a mechanism to limit Fgf8 expression to the CoP. In vivo expression of a dominant negative Sp8 in the CoP indicates that Sp8 maintains expression of Fgf8 and also its effect on area patterning. Ectopic expression of Sp8 in anterior or posterior cortical poles induces significant anterior or posterior shifts in area patterning, respectively, paralleled by changes in expression of gene markers of positional identity. These effects of Sp8 on area patterning oppose those induced by ectopic expression of Fgf8, suggesting that in parallel to regulating Fgf8 expression, Sp8 also activates a distinct signaling pathway for cortical area patterning. In summary, Sp8 and Fgf8 robustly induce one another, and may act to balance the anterior-posterior area patterning of the cortex.