Genetic dissection of the glutamatergic neuron system in cerebral cortex.

Diverse types of glutamatergic pyramidal neurons mediate the myriad processing streams and output channels of the cerebral cortex1,2, yet all derive from neural progenitors of the embryonic dorsal telencephalon3,4. Here we establish genetic strategies and tools for dissecting and fate-mapping subpopulations of pyramidal neurons on the basis of their developmental and molecular programs. We leverage key transcription factors and effector genes to systematically target temporal patterning programs in progenitors and differentiation programs in postmitotic neurons. We generated over a dozen temporally inducible mouse Cre and Flp knock-in driver lines to enable the combinatorial targeting of major progenitor types and projection classes. Combinatorial strategies confer viral access to subsets of pyramidal neurons defined by developmental origin, marker expression, anatomical location and projection targets. These strategies establish an experimental framework for understanding the hierarchical organization and developmental trajectory of subpopulations of pyramidal neurons that assemble cortical processing networks and output channels.

A Policy Approach to Reducing Low-Value Device-Based Procedure Use.

Policy Points Low-value care is common in clinical practice, leading to patient harm and wasted spending. Much of this low-value care stems from the use of medical device-based procedures. We describe here a novel academic-policymaker collaboration in which evidence-based clinical coverage for device-based procedures is implemented through prior authorization-based policies for Louisiana's Medicaid beneficiary population. This process involves eight steps: 1) identifying low-value medical device-based procedures based on clinical evidence review, 2) quantifying utilization and reimbursement, 3) reviewing clinical coverage policies to identify opportunities to align coverage with evidence, 4) using a low-value device selection index, 5) developing an evidence synthesis and policy proposal, 6) stakeholder engagement and input, 7) policy implementation, and 8) policy evaluation. This strategy holds significant potential to reduce low-value device-based care.

The Bond Strength of a Universal Adhesive System with Silane to Lithium Disilicates in Comparison with an Isolated Silane Coupling Agent.

PURPOSE: The aim of this in vitro study was to evaluate the effects of different durations of silane coupling agent application compared to a universal adhesive system regarding the shear bond strength of two ceramic materials. MATERIALS AND METHODS: A total of 120 human molars were ground to the dentinal coronal third and then fixed into an acrylic resin holder. Lithium disilicate specimens were divided into two main groups according to the ceramic type: computer-aided design/computer-aided manufacturing IPS e.max CAD and heat-pressed Initial LiSi Press GC (dimensions of 4 × 3× 3 mm). Each main group was subdivided into 6 subgroups (n = 10) according to the duration of the silane and universal adhesive system application (20, 60, or 120 seconds) on the ceramic surface before cementation; then, the cementation procedures were performed. All specimens were subjected to 5000 thermal cycles at 5 and 55°C before testing. The shear bond strength was measured using a universal testing machine. ANOVA and Scheffe post hoc test multiple comparisons tests were conducted (α = 0.05). RESULTS: The shear bond strength increased as the duration of the silane and universal adhesive system application increased. The highest bond value for each material was found for the silane application at 120 seconds, with a significant difference between 120 and 60, and 20 seconds for both e. max CAD and Initial LiSi materials (p = 0.029 and p ˂ 0.001, respectively). No significant difference was found between 60 and 20 seconds when silane and universal adhesive system were applied for both e. max CAD and Initial LiSi materials (p = 0.169 and p = 0.120, respectively). All groups treated with the silane primer showed significantly higher values than the universal adhesive system for each application time (p ˂ 0.001). CONCLUSION: Increasing the duration of the silane coupling agent and universal adhesive system application to 120 seconds on the ceramic surface before cementation improved the shear bond strength of the ceramic-cement interface. Ceramic pretreatment with silane could be an essential step for bonding ceramic to dentin regardless of silane presence in the universal adhesive system.

Hierarchical genetic interactions between FOXG1 and LHX2 regulate the formation of the cortical hem in the developing telencephalon.

During forebrain development, a telencephalic organizer called the cortical hem is crucial for inducing hippocampal fate in adjacent cortical neuroepithelium. How the hem is restricted to its medial position is therefore a fundamental patterning issue. Here, we demonstrate that Foxg1-Lhx2 interactions are crucial for the formation of the hem. Loss of either gene causes a region of the cortical neuroepithelium to transform into hem. We show that FOXG1 regulates Lhx2 expression in the cortical primordium. In the absence of Foxg1, the presence of Lhx2 is sufficient to suppress hem fate, and hippocampal markers appear selectively in Lhx2-expressing regions. FOXG1 also restricts the temporal window in which loss of Lhx2 results in a transformation of cortical primordium into hem. Therefore, Foxg1 and Lhx2 form a genetic hierarchy in the spatiotemporal regulation of cortical hem specification and positioning, and together ensure the normal development of this hippocampal organizer.

Pattern of dental needs and advice on Twitter during the COVID-19 pandemic in Saudi Arabia.

AIM: To compare and evaluate the influence of the COVID-19 outbreak on tweets related to dental treatment needs and advice of Saudi Twitter users in 2020 by comparing them to the same time-period in 2019. METHODS: Eight independent searches based on dentistry related keywords: "teeth, mouth and gingiva" were carried out within the timeframe between the 23rd of March and the 21st of June for the years 2020 and 2019. Extracted tweets were analyzed by two calibrated examiners as tweets containing expressed dental needs and tweets for dental advice, while spam tweets were excluded. Descriptive analysis was performed to present the overview of the findings using SPSS. Bivariate analysis was performed with Pearson's Chi Square, Fisher's Exact test and Mann-Whitney U test. Statistical significance was set at p ≤ 0.05. RESULTS: A total of 595 tweets from the year 2019 and 714 tweets from the year 2020 were obtained. Overall, combined dental needs and advice tweets, retweets, likes, and replies were higher in 2020 compared to 2019. Dental needs tweets were higher in 2020 compared to 2019, while dental advice tweets were lower in 2020 compared to 2019. Statistically significant differences were found between 2020 and 2019 with regards to dental needs well as with dental advice (p < 0.05). In addition, statistically significant differences were found between 2019 and 2020 with presence of pain, urgency of the dental need and type of advisor (p < 0.05). CONCLUSION: An obvious impact of the pandemic can be seen in the form of increased self-reported dental needs, pain and urgency among the public in Saudi Arabia. This study highlights the importance of social media, specifically Twitter, in expressing the public needs and utilizing it as a platform for education and advice.

Changes in the Excitability of Neocortical Neurons in a Mouse Model of Amyotrophic Lateral Sclerosis Are Not Specific to Corticospinal Neurons and Are Modulated by Advancing Disease.

Cell type-specific changes in neuronal excitability have been proposed to contribute to the selective degeneration of corticospinal neurons in amyotrophic lateral sclerosis (ALS) and to neocortical hyperexcitability, a prominent feature of both inherited and sporadic variants of the disease, but the mechanisms underlying selective loss of specific cell types in ALS are not known. We analyzed the physiological properties of distinct classes of cortical neurons in the motor cortex of hSOD1G93A mice of both sexes and found that they all exhibit increases in intrinsic excitability that depend on disease stage. Targeted recordings and in vivo calcium imaging further revealed that neurons adapt their functional properties to normalize cortical excitability as the disease progresses. Although different neuron classes all exhibited increases in intrinsic excitability, transcriptional profiling indicated that the molecular mechanisms underlying these changes are cell type specific. The increases in excitability in both excitatory and inhibitory cortical neurons show that selective dysfunction of neuronal cell types cannot account for the specific vulnerability of corticospinal motor neurons in ALS. Furthermore, the stage-dependent alterations in neuronal function highlight the ability of cortical circuits to adapt as disease progresses. These findings show that both disease stage and cell type must be considered when developing therapeutic strategies for treating ALS.SIGNIFICANCE STATEMENT It is not known why certain classes of neurons preferentially die in different neurodegenerative diseases. It has been proposed that the enhanced excitability of affected neurons is a major contributor to their selective loss. We show using a mouse model of amyotrophic lateral sclerosis (ALS), a disease in which corticospinal neurons exhibit selective vulnerability, that changes in excitability are not restricted to this neuronal class and that excitability does not increase monotonically with disease progression. Moreover, although all neuronal cell types tested exhibited abnormal functional properties, analysis of their gene expression demonstrated cell type-specific responses to the ALS-causing mutation. These findings suggest that therapies for ALS may need to be tailored for different cell types and stages of disease.

Dmrt5, a Novel Neurogenic Factor, Reciprocally Regulates Lhx2 to Control the Neuron-Glia Cell-Fate Switch in the Developing Hippocampus.

Regulation of the neuron-glia cell-fate switch is a critical step in the development of the CNS. Previously, we demonstrated that Lhx2 is a necessary and sufficient regulator of this process in the mouse hippocampal primordium, such that Lhx2 overexpression promotes neurogenesis and suppresses gliogenesis, whereas loss of Lhx2 has the opposite effect. We tested a series of transcription factors for their ability to mimic Lhx2 overexpression and suppress baseline gliogenesis, and also to compensate for loss of Lhx2 and suppress the resulting enhanced level of gliogenesis in the hippocampus. Here, we demonstrate a novel function of Dmrt5/Dmrta2 as a neurogenic factor in the developing hippocampus. We show that Dmrt5, as well as known neurogenic factors Neurog2 and Pax6, can each not only mimic Lhx2 overexpression, but also can compensate for loss of Lhx2 to different extents. We further uncover a reciprocal regulatory relationship between Dmrt5 and Lhx2, such that each can compensate for loss of the other. Dmrt5 and Lhx2 also have opposing regulatory control on Pax6 and Neurog2, indicating a complex bidirectionally regulated network that controls the neuron-glia cell-fate switch.SIGNIFICANCE STATEMENT We identify Dmrt5 as a novel regulator of the neuron-glia cell-fate switch in the developing hippocampus. We demonstrate Dmrt5 to be neurogenic, and reciprocally regulated by Lhx2: loss of either factor promotes gliogenesis; overexpression of either factor suppresses gliogenesis and promotes neurogenesis; each can substitute for loss of the other. Furthermore, each factor has opposing effects on established neurogenic genes Neurog2 and Pax6 Dmrt5 is known to suppress their expression, and we show that Lhx2 is required to maintain it. Our study reveals a complex regulatory network with bidirectional control of a fundamental feature of CNS development, the control of the production of neurons versus astroglia in the developing hippocampus.Finally, we confirm that Lhx2 binds a highly conserved putative enhancer of Dmrt5, suggesting an evolutionarily conserved regulatory relationship between these factors. Our findings uncover a complex network that involves Lhx2, Dmrt5, Neurog2, and Pax6, and that ensures the appropriate amount and timing of neurogenesis and gliogenesis in the developing hippocampus.

LHX2 Interacts with the NuRD Complex and Regulates Cortical Neuron Subtype Determinants Fezf2 and Sox11.

In the developing cerebral cortex, sequential transcriptional programs take neuroepithelial cells from proliferating progenitors to differentiated neurons with unique molecular identities. The regulatory changes that occur in the chromatin of the progenitors are not well understood. During deep layer neurogenesis, we show that transcription factor LHX2 binds to distal regulatory elements of Fezf2 and Sox11, critical determinants of neuron subtype identity in the mouse neocortex. We demonstrate that LHX2 binds to the nucleosome remodeling and histone deacetylase histone remodeling complex subunits LSD1, HDAC2, and RBBP4, which are proximal regulators of the epigenetic state of chromatin. When LHX2 is absent, active histone marks at the Fezf2 and Sox11 loci are increased. Loss of LHX2 produces an increase, and overexpression of LHX2 causes a decrease, in layer 5 Fezf2 and CTIP2-expressing neurons. Our results provide mechanistic insight into how LHX2 acts as a necessary and sufficient regulator of genes that control cortical neuronal subtype identity. SIGNIFICANCE STATEMENT: The functional complexity of the cerebral cortex arises from an array of distinct neuronal subtypes with unique connectivity patterns that are produced from common progenitors. This study reveals that transcription factor LHX2 regulates the numbers of specific cortical output neuron subtypes by controlling the genes that are required to produce them. Loss or increase in LHX2 during neurogenesis is sufficient to increase or decrease, respectively, a particular subcerebrally projecting population. Mechanistically, LHX2 interacts with chromatin modifying protein complexes to edit the chromatin landscape of its targets Fezf2 and Sox11, which regulates their expression and consequently the identities of the neurons produced. Thus, LHX2 is a key component of the control network for producing neurons that will participate in cortical circuitry.

Lhx2 regulates a cortex-specific mechanism for barrel formation.

LIM homeodomain transcription factors are critical regulators of early development in multiple systems but have yet to be examined for a role in circuit formation. The LIM homeobox gene Lhx2 is expressed in cortical progenitors during development and also in the superficial layers of the neocortex in maturity. However, analysis of Lhx2 function at later stages of cortical development has been hampered by severe phenotypes associated with early loss of function. We identified a particular Cre-recombinase line that acts in the cortical primordium after its specification is complete, permitting an analysis of Lhx2 function in neocortical lamination, regionalization, and circuit formation by selective elimination of Lhx2 in the dorsal telencephalon. We report a profound disruption of cortical neuroanatomical and molecular features upon loss of Lhx2 in the cortex from embryonic day 11.5. A unique feature of cortical circuitry, the somatosensory barrels, is undetectable, and molecular patterning of cortical regions appears disrupted. Surprisingly, thalamocortical afferents innervate the mutant cortex with apparently normal regional specificity. Electrophysiological recordings reveal a loss of responses evoked by stimulation of individual whiskers, but responses to simultaneous stimulation of multiple whiskers were present, suggesting that thalamic afferents are unable to organize the neurocircuitry for barrel formation because of a cortex-specific requirement of Lhx2. We report that Lhx2 is required for the expression of transcription factor paired box gene 6, axon guidance molecule Ephrin A5, and the receptor NMDA receptor 1. These genes may mediate Lhx2 function in the formation of specialized neurocircuitry necessary for neocortical function.

Transcription factor Lhx2 is necessary and sufficient to suppress astrogliogenesis and promote neurogenesis in the developing hippocampus.

The sequential production of neurons and astrocytes from neuroepithelial precursors is a fundamental feature of central nervous system development. We report that LIM-homeodomain (LIM-HD) transcription factor Lhx2 regulates this transition in the developing hippocampus. Disrupting Lhx2 function in the embryonic hippocampus by in utero electroporation and in organotypic slice culture caused the premature production of astrocytes at stages when neurons are normally generated. Lhx2 function is therefore necessary to suppress astrogliogenesis during the neurogenic period. Furthermore, Lhx2 overexpression was sufficient to suppress astrogliogenesis and prolong the neurogenic period. We provide evidence that Lhx2 overexpression can counteract the instructive astrogliogenic effect of Notch activation. Lhx2 overexpression was also able to override and suppress the activation of the GFAP promoter by Nfia, a Notch-regulated transcription factor that is required for gliogenesis. Thus, Lhx2 appears to act as a "brake" on Notch/Nfia-mediated astrogliogenesis. This critical role for Lhx2 is spatially restricted to the hippocampus, because loss of Lhx2 function in the neocortex did not result in premature astrogliogenesis at the expense of neurogenesis. Our results therefore place Lhx2 as a central regulator of the neuron-glia cell fate decision in the hippocampus and reveal a striking regional specificity of this fundamental function within the dorsal telencephalon.

A comparative analysis of sphenoid and frontal sinuses using cone beam computed tomography for sex determination.

Objectives: This study aimed to evaluate linear measurements of the frontal sinus (FS) and sphenoid sinus (SS) for sex identification on cone beam computed tomography (CBCT) images. Methods: A comparative CBCT analysis was conducted on 200 full field of view (FOV) scans taken as part of routine dental investigations. Dimensions of the bilateral frontal and sphenoid sinuses were measured. Intra- and interobserver reliability were calculated. Independent t tests were used to compare the various parameters between sexes. Stepwise discriminant function analysis was used to determine sex. Additionally, the receiver operating characteristic (ROC) curve, area under the curve (AUC), sensitivity, and specificity were also determined. A p value < 0.05 was considered significant. Results: A total of 200 CBCT scans were included in the study. The mean age (±SD) among males was 25.66 (±7.11) and that among females was 24.64 (±5.12). The ROC curve revealed that the right length of the frontal sinus showed the greatest accuracy in sex identification in comparison to other linear measurements of the FS and SS. The results of our study indicated that the equation obtained from stepwise discriminant function analysis can aid in sex determination with an accuracy of 76.5 %. Conclusion: Our findings support the sexual dimorphism of linear measurements of FS and SS. There was an improvement in the accuracy of sex prediction when the linear measurements of FS and SS were considered in combination rather than in isolation. The derived equation can be an adjunctive tool for sex identification for the representative population.

A randomised controlled trial to evaluate the effect of GandhakaRasayana rectal suppository in post operative pain management in ano-rectal disorders.

BACKGROUND: Poorly managed post-operative pain can lead to complications and prolonged rehabilitation. Pain Management after ano-rectal surgery becomes important as it could hamper day to day activities, disturb sleep, alter appetite and bowel evacuations and decrease the quality of life. According to Acharya Sushrutha, pain (Shoola) cannot be produced without Vata dosha and Shoola (pain) is inevitable after Shastra (surgical) Karma (procedure) for which Basti (enema) is usually the management of choice. Rectal suppositories are one such dosage form that are extensively used in post-operative pain management especially after ano-rectal surgery. MATERIALS AND METHOD: In the study, a total of 40 patients who fulfilled the inclusion criteria were randomly divided to two groups comprising of 20 patients each. Patients of Group A were treated with Gandhaka Rasayana rectal suppository and Group B were treated with Diclofenac Sodium rectal suppository for post-operative 5 days. RESULTS: The overall comparative results revealed a statistically significant improvement of 85% in Group A and 80.39% in Group B. Gandhaka Rasayana which is Tridoshashamaka, Vatamaya Nivaraka (ameliorates diseases caused by Vata dosha), Agnivardhaka (improves appetite and metabolism) and Shoolahara (reduces pain) attains micro particle size with 88 Bhavana (trituration) that can be readily absorbed by the rectal mucosa to exhibit the required therapeutic action. CONCLUSION: The Bhavana Dravya (medium of trituration) used in the preparation of Gandhaka Rasayana have proven analgesic, anti-inflammatory, anti-bacterial action and is also said to promote wound healing. The present study reveals that there is significant effect of Gandhaka Rasayana rectal suppositories in managing post-operative pain of ano-rectal disorders.

The Effect of Sealer Application Methods on Voids Volume after Aging of Three Calcium Silicate-Based Sealers: A Micro-Computed Tomography Study.

During obturation, air voids are undesirable as they may provide shelter for microorganisms or passage for fluids. This study aimed to compare the occurrence of voids between three calcium silicate-based sealers (CSBSs) (MTA-Fillapex, BioRoot-RCS, Bio-C) and the change in their volume after aging. In addition, we aimed to compare voids when using two sealer application methods: lentulo-spiral (LS) and gutta-percha (GP) cone. Thirty extracted mandibular premolars (n = 30) were endodontically prepared and obturated using single GP cone (SGPC) technique. Each sealer was applied to 10 teeth (n = 10) using LS or GP. Micro-computed tomography (micro-CT) was used to quantify the volume of root filling and voids before and after 8-week storage in a phosphate-rich medium. The percentage of root filling and voids were compared between the groups using a Mann-Whitney U test and Kruskal-Wallis test with a Bonferroni correction. Before aging, the percentages of root filling volume after obturation were comparable with no significant differences between sealers (p = 0.325) or application methods (p = 0.950). After aging, the voids' volume increased significantly in all sealers (p ≤ 0.05). However, no significant differences were found between sealers (p = 0.302). In conclusion, voids in CSBSs may not reduce in size with aging; hence, SGPC should be carefully selected for suitable cases.

Temporally divergent regulatory mechanisms govern neuronal diversification and maturation in the mouse and marmoset neocortex.

Mammalian neocortical neurons span one of the most diverse cell type spectra of any tissue. Cortical neurons are born during embryonic development, and their maturation extends into postnatal life. The regulatory strategies underlying progressive neuronal development and maturation remain unclear. Here we present an integrated single-cell epigenomic and transcriptional analysis of individual mouse and marmoset cortical neuron classes, spanning both early postmitotic stages of identity acquisition and later stages of neuronal plasticity and circuit integration. We found that, in both species, the regulatory strategies controlling early and late stages of pan-neuronal development diverge. Early postmitotic neurons use more widely shared and evolutionarily conserved molecular regulatory programs. In contrast, programs active during later neuronal maturation are more brain- and neuron-specific and more evolutionarily divergent. Our work uncovers a temporal shift in regulatory choices during neuronal diversification and maturation in both mice and marmosets, which likely reflects unique evolutionary constraints on distinct events of neuronal development in the neocortex.

Signals from the edges: the cortical hem and antihem in telencephalic development.

The early cortical primordium develops from a sheet of neuroepithelium that is flanked by distinct signaling centers. Of these, the hem and the antihem are positioned as longitudinal stripes, running rostro-caudally along the medial and lateral faces, respectively, of each telencepahlic hemisphere. In this review we examine the similarities and differences in how these two signaling centers arise, their roles in patterning adjacent tissues, and the cells and structures they contribute to. Since both the hem and the antihem have been identified across many vertebrate phyla, they appear to be part of an evolutionary conserved set of mechanisms that play fundamental roles in forebrain development.

A case series of second-degree burn patients managed with Patoladi vikeshika, an Ayurvedic contact layer dressing.

Management of burn injury is a challenging task as it can lead to considerable amount of agony and disability to the victims. An estimated annual burn incidence in India is 6-7 million. Depending on the degree of burn or the thickness of skin involved, the healing period will vary from 1 to 3 weeks. The aims of dressing in burn injury are to decrease the agony from pain in the wound, to protect or isolate the burn wound from the irritation caused by the dress worn and external environment, and to the hasten the healing of the wound. There are several established advanced dressings in use which hold the qualities of ideal contact layer dressing. Patoladi vikeshika is an attempt to bring in such contact layer dressings in Ayurveda.Patoladi vikeshika was prepared by impregnating Patoladi sikta taila, which was prepared as per Taila paka vidhi, over 10 cm × 10 cm sterile gauzes. These impregnated gauzes were packed and sterilized. The prepared Vikeshika was applied as a contact layer dressing over second-degree burn wounds of 3 patients, after cleaning with normal saline once in every 48 h. Within 4-5 dressings, wounds healed completely without any complications like infection. Patoladi vikeshika seems to have the qualities of an ideal contact layer dressing and therapeutically it has shown good results in the above cases.

Dental Care in the Arab Countries During the COVID-19 Pandemic: An Infodemiological Study.

BACKGROUND: Twitter is a powerful platform which could be used to reflect on the demand and supply of dental services during a pandemic. The aim of this study was to examine the nature and dissemination of COVID-19 information related to dentistry on Twitter platform Arabic database during the COVID-19 pandemic. METHODOLOGY: One hundred and fifty independent searches with a combination of keywords for both COVID-19 and dentistry from a preselected Arabic keyword were carried out for the period from the 2nd of March (first confirmed cases of COVID-19) to the 6th of July 2020. Tweets were filtered to remove duplicate and unrelated tweets. The suitable tweets were 1,150. After calibration, two examiners coded the tweets following two main themes: COVID-19 and oral health-related information. Tweets were then compared with COVID-19 daily events in the Arab countries as reported by the World Health Organization (WHO). Descriptive analysis was performed to present the overview of the findings using Microsoft Excel. RESULTS: The most retweeted information was the help with urgent consultation or emergency dental treatment during COVID-19 tweeted by a dentist. There were 673 retweets and 1,116 likes of this tweet. The most common tweets related to oral health were needs of dental treatment (n=462, 39.5%) of which, toothaches or wisdom tooth problems constituted 48% of the related tweets. CONCLUSION: Based on the results of this study, it is obvious that social media users reacted to the COVID-19 threat to dental practices. Twitter as one of the social media platforms served as a connection between dental health professionals and patients.

In vivo Perturb-Seq reveals neuronal and glial abnormalities associated with autism risk genes.

The number of disease risk genes and loci identified through human genetic studies far outstrips the capacity to systematically study their functions. We applied a scalable genetic screening approach, in vivo Perturb-Seq, to functionally evaluate 35 autism spectrum disorder/neurodevelopmental delay (ASD/ND) de novo loss-of-function risk genes. Using CRISPR-Cas9, we introduced frameshift mutations in these risk genes in pools, within the developing mouse brain in utero, followed by single-cell RNA-sequencing of perturbed cells in the postnatal brain. We identified cell type-specific and evolutionarily conserved gene modules from both neuronal and glial cell classes. Recurrent gene modules and cell types are affected across this cohort of perturbations, representing key cellular effects across sets of ASD/ND risk genes. In vivo Perturb-Seq allows us to investigate how diverse mutations affect cell types and states in the developing organism.

Early dorsomedial tissue interactions regulate gyrification of distal neocortex.

The extent of neocortical gyrification is an important determinant of a species' cognitive abilities, yet the mechanisms regulating cortical gyrification are poorly understood. We uncover long-range regulation of this process originating at the telencephalic dorsal midline, where levels of secreted Bmps are maintained by factors in both the neuroepithelium and the overlying mesenchyme. In the mouse, the combined loss of transcription factors Lmx1a and Lmx1b, selectively expressed in the midline neuroepithelium and the mesenchyme respectively, causes dorsal midline Bmp signaling to drop at early neural tube stages. This alters the spatial and temporal Wnt signaling profile of the dorsal midline cortical hem, which in turn causes gyrification of the distal neocortex. Our study uncovers early mesenchymal-neuroepithelial interactions that have long-range effects on neocortical gyrification and shows that lissencephaly in mice is actively maintained via redundant genetic regulation of dorsal midline development and signaling.