5 EGTA, 10 Na2-phosphocreatine, 4 Mg-ATP, and 0 4 Na2-GTP (pH 7 3

5 EGTA, 10 Na2-phosphocreatine, 4 Mg-ATP, and 0.4 Na2-GTP (pH 7.3, 292 mOsm). The electrode resistance ranged from 7 to 12 MΩ. Electrodes were introduced through a craniotomy, usually 2 mm wide and 6 mm long, at Horsley-Clarke posterior 1–7 mm and near the midline. The electrodes were placed 500–700 μm apart at the cortical surface, angled at 25° relative to one

another so that their tips approached each other as they were driven into the brain. Warm agar solution (3% in saline) was applied to cortical surface to reduce brain movement. Cell pairs were included in the analysis only if the resting Vm of each cell was stable and was more hyperpolarized than −45 mV for long enough (15–60 min) so that we could record data from multiple sets of stimulus presentation. Vm was recorded using an Axoclamp 2A amplifier in bridge mode, anti-alias filtered and sampled at 20 kHz. To reduce capacitive coupling between the two selleck chemicals electrodes, a grounded metal plate was inserted between them. In some experiments (Figure S5), one recording from a pair

was left in juxtacellular mode. For each pair, nonoverlapping blocks (1 s in length) of the spontaneous data were prepared for cross-correlation and spectral analysis through a few steps: (1) spike removal by interpolating the beginning and the end of spikes (Bruno and Sakmann, 2006), (2) subtraction of the Dasatinib DC component so that each block had zero mean, (3) resampling the data from 20 kHz to 4096 Hz, (4) removal of line noise (60 Hz and its harmonics) using Chronux routines (http://chronux.org), and (5) smoothing by Savitzky-Golay mafosfamide filtering (Matlab sgolayfilt function). For visually evoked data, we used only the first 1 or 2 s of the responses (0.25–2.25 s after stimulus onset or 0.25–1.25 s if the stimulation duration was less than 2.25 s).

In addition to the steps listed above for spontaneous data, for each stimulus condition, we also subtracted the stimulus-averaged Vm response in order to remove stimulus-locked component. This step was not critical for complex cells, since by definition they show little temporal modulation at the stimulus frequency (or higher harmonics). After the above preparation, cross-correlation of Vm1Vm1 and Vm2Vm2 for each block of data was calculated as follows (Matlab xcorr function): R12(τ)=∑t=1N−τVm1(t+τ)Vm2(t)∑t=1NVm12(t)∑t=1NVm22(t),τ≥0;R12(τ)=R21(−τ),τ<0where N is the total number of data points (4096 for 1 s block) and τ is the time lag. Cross-correlations of all blocks were then averaged for each stimulus condition. The peak of the cross-correlation was taken as the maximum within 10 ms of zero time lag; the full width of the correlation was measured at half height. Since subtraction of mean response eliminated most stimulus-locked components, the cross-correlation for shift-predictor data (shifted by one trial) was flat (not shown), with no significant peaks near zero time lag.

K and by the Friedrich Schiedel Foundation A K is a Carl von L

K. and by the Friedrich Schiedel Foundation. A.K. is a Carl von Linde Senior Fellow of the Institute for Advanced Study of the Technische Universität München. N.L.R. was supported by the DFG (IRTG 1373). M.N. was supported

by the Japan Society for the Promotion of Science Postdoctoral Fellowships for Research Abroad. “
“The polarized architecture of axon and dendrites is critical for the neuron to function as a computational unit in the nervous system. During early development, the initial establishment of axon/dendrite polarity may depend on intrinsic determinants within the neuron and extrinsic factors from its environment (Arimura and Kaibuchi, 2007 and Barnes et al., 2008). The intrinsic determinant may accumulate asymmetrically in the cytoplasm as a result of the last mitotic division (de Anda et al., 2005) or selleck chemicals llc a self-amplification process (Arimura and Kaibuchi, 2007 and Shelly et al., 2007) that acts upon local stochastic fluctuation of its distribution or activity (Jacobson et al., 2006), leading to axon/dendrite differentiation. Many extrinsic factors, including gradients of diffusible or bound chemical factors in the developing tissue, may polarize the neuron by setting the axis of the asymmetric division, the direction of axon/dendrite initiation from the soma, and the morphology and orientation of axonal and dendritic arbors (Polleux et al., 1998, Polleux et al., 2000, Noctor et al., IWR1 2004, Adler et al.,

2006, Hilliard and Bargmann, 2006 and Yi et al., 2010). In this study, we focused on the role of Sema3A, a secreted protein of the class III semaphorin superfamily, in axon/dendrite initiation during the early phase of neuronal polarization, prior to its effects as a chemotropic factor for axon/dendrite guidance (Polleux et al., 2000) and neuronal migration (Chen et al., 2008). In the absence of asymmetric extrinsic cues, dissociated embryonic hippocampal neurons undergo aminophylline spontaneous polarization in culture—from a cell exhibiting several morphologically similar neurites to a mature neuron exhibiting a single axon and multiple dendrites within few days and capable of forming functional synapses within 1–2 weeks (Dotti

and Banker, 1987 and Dotti et al., 1988). Using this culture system, previous studies have shown that local activation of either PI3-kinase (Shi et al., 2003 and Yoshimura et al., 2005) or cAMP/PKA (Shelly et al., 2007 and Shelly et al., 2010) signaling pathways can trigger axon differentiation, through recruitment or phosphorylation of proteins such as plasma membrane ganglioside sialidase (PMGS) (Da Silva et al., 2005), shootin1 (Toriyama et al., 2006), and LKB1 (Barnes et al., 2007 and Shelly et al., 2007). These proteins in turn regulate downstream effectors, such as the PAR3/PAR6/aPKC complex (Shi et al., 2003), GSK-3β (Yoshimura et al., 2005), Rho family of small GTPases (Schwamborn and Püschel, 2004), and CRMP2 (Inagaki et al.

The B2P6 chimera was completely insensitive to ion exchanges (pea

The B2P6 chimera was completely insensitive to ion exchanges (peak currents, relative to NaCl: 94% ± 1% for CsCl; 95% ± 5%, NaNO3, n = 3, not shown). Glutamate (10 mM) activated a large steady state current at the B2P6 chimera

(21% ± 1% of peak, n = 15 patches), reminiscent of the Willardiine series of partial agonists (Jin et al., 2003). To check that glutamate remains a full agonist at the B2P6 chimera, we estimated open probability using noise analysis (Figures S2A–S2D). Wild-type GluA2 receptors have a high peak open probability (77% ± 7%, n = 5 patches), and the peak open probability of the B2P6 chimera was not significantly different (65 ± 5%, n = 5 patches; p > 0.05, randomization test). Weighted single-channel conductance was also similar (WT A2: 18 ± 3 pS; B2P6: Bioactive Compound Library datasheet 16 ± 1 pS). Additionally, we checked if quisqualate, which activates a larger current than glutamate in GluA2 mutants where domain closure is hindered (Robert et al., 2005), could activate Pexidartinib order bigger responses than glutamate at the B2P6 construct (Figures S2E and S2F). Currents activated by quisqualate (2 mM) and glutamate (10 mM) were similar in amplitude (Quis. peak current: 92% ± 8% of that evoked by 10 mM glutamate, n = 5 patches), suggesting that domain closure in

the B2P6 channel is normal. These results exclude spurious partial agonism as an explanation for fast recovery, and suggest that the large steady state current in the B2P6 chimera is due to recovery that is even faster than wild-type GluA2. Our recordings of the B2P6 and B6P2 chimeras displayed striking features that we reasoned could constrain parameters in simulations of receptor kinetics and thereby provide insight to the molecular mechanisms determining recovery from desensitization. Our aim was to identify if individual

kinetic transitions could explain the observed behavior and, by comparing with existing biophysical studies (Robert et al., 2005 and Zhang et al., 2008), pinpoint the region of the LBD most likely to control recovery. Using a simplified why model of GluR activation (see Figure 2A and Supplemental Experimental Procedures), we tried three scenarios to account for changes in recovery rate. First, we varied the lifetime of a deep desensitized state (AD2), from which agonist dissociation was very slow. Second, alterations in the bound lifetime of glutamate might change recovery, and we simulated this on two backgrounds, with initially slow and fast recovery, respectively. Finally, we tested the hypothesis that the equilibrium between resting (AR) and desensitized states (AD) differs between AMPA and kainate receptors. The rate of recovery from desensitization was sensitive to rate changes in each case.

As both PDGF and EGF pathways are frequently affected in human br

As both PDGF and EGF pathways are frequently affected in human brain tumors, dissecting the differing effects of these two stimuli on the properties of immature cells may offer insight into the invasive and proliferative properties of distinct classes of gliomas. In fact, recent work suggests that deregulation of proliferation or oncogenic mutations within progenitor populations of the VZ-SVZ

could lead to brain tumor formation (Persson et al., 2002, Zhu et al., 2005, Zheng et al., 2008, Alcantara Llaguno et al., 2009 and Jacques et al., 2010). Another subset of the receptor tyrosine kinase family, ephrin receptors, is also selleck kinase inhibitor active in the adult VZ-SVZ. Eph receptors and

their transmembrane ephrin ligands function in guidance of migratory cells and establishment of boundaries in developing tissues. Within the adult VZ-SVZ, both EphB and EphA receptors are expressed, and ephrin signaling appears to impact both type B cell proliferation and type A cell migration (Conover et al., 2000, Liebl et al., 2003 and Ricard et al., 2006). Infusion of EphB2 ligand results in disrupted and aberrant chains of migratory neuroblasts and also in increased BrdU incorporation by type B1 cells. Intriguingly, infusion also appears to increase the number of stem cells contacting the ventricle, possibly indicating increased Selleck FK228 type B1 cell activation. More recently, EphB2 signaling has also been suggested to act downstream of Notch signaling to maintain ependymal cell identity and regulate the conversion of ependymal cells to astrocytes after injury to the ventricular face (Nomura et al., 2010). EphA4 signaling has been proposed to Levetiracetam act as an anti-apoptotic signal within the adult VZ-SVZ, as removal of ephrinB3 in the adult results

in increased apoptosis (Furne et al., 2009). EGFR signaling has also been proposed to modulate Notch signaling—a fundamental pathway in nervous system development (Aguirre et al., 2010). Notch is essential for maintaining asymmetric division and stem cell pools in multiple tissues (Maillard et al., 2003 and Mizutani et al., 2007). In the adult VZ-SVZ, loss of Notch signaling compromises stem cell self-renewal, while activation of this pathway enhances neurosphere formation (Hitoshi et al., 2002 and Alexson et al., 2006). Postnatal deletion of Numb/Numblike, which inhibit Notch signaling by mediating degradation of the Notch protein, has also been shown to affect the VZ-SVZ niche. Acute deletion of Numb/Numbl in nestin-positive VZ-SVZ cells resulted in extensive defects in maturation of the neonatal VZ/SVZ, alterations in ependymal cell maturation and adhesion, and decreased neuroblast survival, likely due to excess Notch activity (Kuo et al., 2006).

, 2007), suggesting that OBPs play an important role in ecologica

, 2007), suggesting that OBPs play an important role in ecological diversification. In our view, elucidating the precise role of this interesting gene family should be a prioritized task for the field. Like the OBPs, the gene family encoding odorant receptors (ORs) in insects is also an insect exclusive radiation. The ORs form a large and highly divergent gene family (Clyne et al., 1999 and Vosshall et al., 1999), selleckchem which shows no homology to the OR families

of vertebrates and nematodes. The insect ORs and the related gustatory receptors (GRs, Clyne et al., 2000 and Scott et al., 2001) together form an arthropod-specific chemoreceptor superfamily, in which the ORs constitute a single highly expanded branch (Robertson et al., 2003). Members of this superfamily essentially share no homology to any known gene family, and encodes for seven transmembrane-domain receptors with an inverted transmembrane topology learn more as compared to the G protein-coupled olfactory receptors of vertebrates (Benton et al., 2006). In contrast to the ORs of vertebrates, the insect ORs form heteromeric

complexes typically composed of a single ligand-binding OR (Störtkuhl and Kettler, 2001 and Dobritsa et al., 2003, but see Goldman et al., 2005) and the OR coreceptor Orco (Vosshall et al., 2000 and Larsson et al., 2004). Orco acts as a chaperone (Larsson et al., 2004) and also takes part in signal transduction (Sato et al., 2008 and Wicher et al., 2008). The rise of the OR family is assumed to date back to the early

Devonian and the first insects as an adaptation to terrestrial life not (Robertson et al., 2003). However, one could also envision that the OR radiation occurred at a later stage (perhaps first with the rise of Neoptera); being driven by the diversification of vascular plants and the increasing abundance of volatile chemicals in the environment. The latter scenario is in our view more likely. Insect ORs form a large and highly divergent gene family, with no close orthologies (apart from Orco) or apparent subfamily structure conserved across insect orders Figure 3). Thus-far-identified OR repertoires range in size from ten in Phthiraptera (i.e., lice, Kirkness et al., 2010) to ∼200–400 in Hymenoptera (i.e., bees, ants, and wasps; Robertson et al., 2010 and Wurm et al., 2011). As with the OBPs, the OR family is characterized by species-specific expansions of single genes or gene subfamilies. Recently duplicated OR loci gain novel functions through positive selection, presumably driven by needs arising from host shifts or host specializations (see below, Gardiner et al., 2008). These processes may also render previous adaptations in the chemosensory repertoire void, resulting in the loss of OR genes that no longer serve a functional purpose. Analysis of the OR repertoires of the five closest relatives of D.

A single administration of FGF2 on PND1 increased cocaine

A single administration of FGF2 on PND1 increased cocaine

self-administration in adulthood (Turner et al., 2009). This effect is selective as there were no associated differences in spatial or appetitive learning. Moreover, there were no sustained changes in gene expression in the dopaminergic system seen in the adult animal. This does not preclude the possibility that early exposure to FGF2 primed the dopaminergic system, which in turn led to increased drug-taking behavior in adulthood. Whether the actions of early life FGF2 are mediated via dopamine Selleck Pfizer Licensed Compound Library or other mechanisms, the ability of this growth factor to enhance drug-taking behavior identifies it as a molecular antecedent of vulnerability for substance abuse. Given the fact that drugs of abuse interact with stress, it is notable that both stress and drugs of abuse converge to modulate FGF2 expression. Thus, in the prefrontal cortex, acute stress potentiated the cocaine-induced increase in FGF2 expression, whereas prolonged stress prevented the response of FGF2 to cocaine (Fumagalli et al., 2008). In the striatum, the cocaine-induced FGF2 response was only increased following repeated stress. In summary, FGF2 appears to promote both the initial vulnerability and the sequelae of substance abuse. Its administration in early life enhances the propensity for self-administration of drugs KU57788 of abuse in adulthood.

In turn, repeated exposure to drugs of abuse induces FGF2 expression especially in the dopaminergic system, and this induction is required for the development of sensitization. Overall, FGF2, along with FGFR1, can be construed as molecular

factors that modulate emotional reactivity—higher FGF2 levels render animals more prone to novelty and drug taking behavior, while lower FGF2 levels render animals less prone to drug seeking but more prone to anxiety- and depression-like behaviors. Other molecules, such as NCAM, can also interact with the FGF receptors and appear to play a role in the control of emotionality. NCAM polymorphisms have been observed in conjunction with mood disorders 3-mercaptopyruvate sulfurtransferase in humans (Atz et al., 2007; Vawter, 2000). In animal models, NCAM responds to stress system activation, with upregulation of its expression in the cortex following acute corticosterone injections and downregulation following chronic corticosterone (Sandi and Loscertales, 1999)—a pattern that mirrors the regulation of FGF2 by this stress hormone. However, the isoform of NCAM is also important. For example, exposure to a stressful situation decreased NCAM-180 levels in the hippocampus without affecting the levels of NCAM-140 or NCAM-120 (Sandi et al., 2005). Finally, posttranslational modifications of NCAM (polysialylation) can also be affected by stress (Cordero et al., 2005). Similar to FGF2, FGL, a fragment of the NCAM structure (Carafoli et al., 2008; Ditlevsen et al.

, 2008; Frith and Frith, 1999, 2006; Hampton et al , 2008; Saxe,

, 2008; Frith and Frith, 1999, 2006; Hampton et al., 2008; Saxe, 2006). While vmPFC responses to valuation and goal-directed choice are the subject of several computational theories (Boorman et al., 2009; Hare et al., 2011; Hunt et al., 2012; Levy and Glimcher, 2011; Lim et al., 2011),

only scant attention has been given to computational mechanisms underlying dmPFC social responses (Behrens et al., 2008; Hampton et al., 2008; Yoshida et al., 2010). One possibility is that the ability to impute the intentions (Frith and Frith, 2006) and predict the actions (Behrens et al., 2008) of others derives from the same mechanisms that allow us to reflect on our own goals and actions (Amodio and Frith, 2006; Buckner and Carroll, 2007; Mitchell, 2009). Such a theory is appealing, as it would allow a computational understanding of goal-directed choice to be extended to social inferences. Ruxolitinib However, this idea is difficult to reconcile with the existence of brain regions that appear specialized for processing self and other. Instead, it raises the intriguing possibility that a functional specialization in rostromedial prefrontal cortex (and in related temporoparietal cortex; Mitchell, 2008; Saxe and Wexler, 2005) is driven more by differences

Dasatinib molecular weight between choices that are executed versus those that are imagined or modeled. Teasing these two possible functional architectures apart is problematic as they are almost always aligned in cognitive tasks, where self-choices tend to be executed and others’ actions and intentions modeled. Here, we describe neural signals that compute the choice preferences of another individual, whether or not they are relevant to the current choice. These signals precisely mirror well-studied signals reflecting

personal choice preferences. Furthermore, by designing situations in which values of self and other may be either modeled or executed, we show that the functional gradient in the medial prefrontal cortex does not align with the individual, but is dependent on whether choices are executed by the subject or instead are modeled without overt execution. not To examine neural computations for self and others in medial prefrontal cortex, we designed a delegated intertemporal decision-making task (Figure 1A). Subjects chose between a large monetary reward delivered later, and a small reward delivered sooner. Critically, we asked subjects to choose for themselves in some trials, but in other trials to choose on the basis of what a partner participant would have chosen in the same context (Figure 1A). It is known that different individuals display significant variability in their preferences, with “low-discounters” preferring to wait for a later higher-value option and “high-discounters” preferring the more immediate smaller reward (Kable and Glimcher, 2007).

, 2000) That GluN2B receptor activity is required for both the m

, 2000). That GluN2B receptor activity is required for both the maintenance of silent synapses as well as inducing LTP and synapse maturation may initially seem contradictory. However, differences in Ca2+ influx during low-level or basal activity versus strong activity may activate different signaling pathways. Indeed, it is well established that an www.selleckchem.com/products/Temsirolimus.html LTP-inducing stimulus can convert AMPAR-silent synapses into AMPAR-signaling synapses (Durand et al., 1996, Isaac et al., 1997 and Liao et al., 1995), while, in neonatal neurons, AMPAR silencing can be induced with an LTD-like protocol (Xiao et al., 2004). Our results here suggest that low-level activation of GluN2B-containing

NMDARs suppresses AMPAR insertion into synaptic sites, possibly through an LTD-like mechanism at developing hippocampal neurons. Taken together, these observations demonstrate

a fundamental developmental role for the NMDA receptor subunit switch in tightly regulating AMPAR recruitment at multiple levels. Due to the perinatal lethality of the germline GluN2B KO, many groups have recently examined the effects of more selective GluN2B deletion. For example, dissociated cortical cultures from GluN2B KO mice showed an increase in mEPSC amplitude (Hall et al., 2007), in contrast to our findings, though frequency appeared to increase but was not reported. In addition, RNA interference (RNAi) was used to block GluN2B expression with similar effects; however, this manipulation resulted in a complete loss of all NMDAR current

until (Hall et al., 2007). LDN-193189 order This discrepancy may be related to the high excitatory drive of dissociated cultures, direct or indirect off-target effects of the GluN2B RNAi on GluN2A expression, or it may suggest that their experimental system may not be broadly generalizable to synapses developing in intact networks. Interestingly, deletion of GluN2B in the adult hippocampus had no effect on mEPSC amplitude or frequency (von Engelhardt et al., 2008), suggesting a purely developmental effect. Due to the increase in mEPSC frequency after deletion of GluN2B, we analyzed dendritic anatomy and spine density and saw no significant changes in overall dendrite branching or length in any of the conditions. Previous reports of GluN2 subunit effects on dendritic arborization have revealed subtle changes in dendritic arbor growth and patterning, but not significant changes in overall length (Espinosa et al., 2009 and Ewald et al., 2008). We did, however, observe a small significant decrease in spine density with the deletion of GluN2B. This reduction in spines after the deletion of GluN2B has been reported previously (Akashi et al., 2009, Espinosa et al., 2009 and Gambrill and Barria, 2011) and may be related to the unfettered early expression of GluN2A (Gambrill and Barria, 2011), as deletion of GluN1 does not alter spine density (Figure 7; Figure S5) (Adesnik et al., 2008).

, 2005 and Gunaydin et al , 2010) to toxicity (Gradinaru et al ,

, 2005 and Gunaydin et al., 2010) to toxicity (Gradinaru et al., 2008, Gradinaru et al., 2010 and Zhao et al., 2008) to challenges linked to light delivery in vivo (Aravanis et al., 2007 and Adamantidis et al., 2007). A long process of tool engineering and substantial development of enabling technologies was required over the next several years. The key properties of these microbial optogenetic tools relate to the ecology of their original host organisms, find more which respond to the environment using seven-transmembrane proteins encoded by the type I

class of opsin gene (Yizhar et al., 2011b). Type I opsins are protein products of microbial opsin genes and are termed rhodopsins when bound to retinal. However, in typical heterologous expression experiments the precise composition of retinoid-bound states is uncharacterized.

Therefore in the setting of neuroscience application, the tools are conservatively referred to as opsins (a more accurate and convenient shorthand for common use, since only “opsin” correctly applies to the genes as well as to the protein products). These proteins are distinguished from their learn more mammalian (type II) counterparts, in that they are single-component light-sensing systems; the two operations—light sensing and ion conductance—are carried out by the same protein. The first identified, and still by far the best studied, type I protein is the haloarchaeal proton pump bacteriorhodopsin (BR; Figure 1A; Oesterhelt and Stoeckenius, 1971, Oesterhelt and Stoeckenius, 1973 and Racker and Stoeckenius, 1974). Under low-oxygen conditions, BR is highly expressed in haloarchaeal membranes and serves as part of an alternative energy-production system, pumping protons from the cytoplasm to the extracellular medium to generate a proton-motive force to drive ATP synthesis (Racker and Stoeckenius, 1974 and Michel and Oesterhelt, 1976). These light-gated proton pumps have since

also been found in a wide range of marine proteobacteria as well as in other kingdoms of life, where they employ similar photocycles (Béjà et al., 2001 and Váró et al., 2003) and have been hypothesized to play diverse roles in cellular secondly physiology (Fuhrman et al., 2008). A second class of microbial opsin genes encodes halorhodopsins (Figure 1A). Halorhodopsin (HR) is a light-activated chloride pump first discovered in archaebacteria (Matsuno-Yagi and Mukohata, 1977). The operating principles of halorhodopsin (HR) are similar to those of BR (Essen, 2002), with the two main differences being that halorhodopsin pumps chloride ions and its direction of transport is from the extracellular to the intracellular space. Specific amino acid residues have been shown to underlie the differences between BR and HR in directionality and preferred cargo ion (Sasaki et al., 1995).

In this region, the Sox2+ NPC compartment displayed a 2- to 3-fol

In this region, the Sox2+ NPC compartment displayed a 2- to 3-fold increased expression of N-cadherin and the number of differentiated neurons formed was reduced by ∼38% ( Figures 7N–7Q, 7R–7U, and 7AE). NeuN+ neurons were also interspersed within the VZ comparable to the defects seen in the Foxp4LacZ/LacZ mutant spinal cord and the chick Foxp2/4 double-knockdown experiments ( Figures 2L–2O and 7H, 7L, 7Q, and 7U). Foxp4 mutant forebrains frequently lacked lateral ventricles, with medial and

lateral cortices displaying Docetaxel cell line unusually contiguous contacts along their apical membranes, resulting in convolution and invagination of the neuroepithelium ( Figures 7N–7P, 7R–7T, S8S–S8U, and S8X–S8Z). Sonic hedgehog, whose loss of function is commonly associated with holoprosencephaly, was nevertheless present in all embryos analyzed, and the dorsoventral position of different NPC subtypes was generally intact ( Figures S8U, S8Z, and S8AA–S8AD). This feature of the Foxp4 mutants is notably similar to the phenotype of mice in which AJ components such as Cdc42 have been inactivated ( Cappello et al., 2006 and Chen et al., 2006). Finally, we misexpressed Foxp4 in the developing

cortex and found that it potently suppressed the expression of N-cadherin, Sox2, β-catenin, and other components of AJs, much like the effects seen in the chick spinal cord 3MA (Figures 7V–AC and 7AF). Consequently, the number of Tbr2+ neurons was elevated ∼2-fold and formed ectopic clusters within and adjacent to the VZ (Figures 7Y, 7AC,

and 7AF). Collectively, these results suggest that the suppressive effects of Foxp4 and Foxp2 on NPC adhesion might play a more general role in regulating progenitor maintenance throughout the developing CNS. The polarized organization and proliferation of neuroepithelial progenitors depends on the formation of AJs between NPCs. These contacts act as a self-supporting stem cell niche to maintain cells in an undifferentiated state. Our results identify Foxp4 and Foxp2 as components of a gene regulatory network that balances the assembly and disassembly of AJs to respectively promote NPC proliferation and differentiation. In the normal also course of MN development, Foxp4 levels increase as NPCs shed their adhesive contacts and migrate away from the VZ (Figure 8A). When Foxp proteins are artificially elevated, N-cadherin and Sox2 expression are suppressed, leading to the dissolution of AJs, cytoplasmic distribution of Numb, and ectopic neurogenesis within the VZ (Figure 8B). In contrast, the combined loss of Foxp2 and Foxp4 increases N-cadherin expression and retains NPCs in an undifferentiated, neuroepithelial state (Figure 8C). Together, these findings provide important insights into the developmental programs that influence how NPCs interact with themselves and their environment to regulate the size and shape of the nervous system.