RESUMO
Rapid phasic activity of midbrain dopamine neurons is thought to signal reward prediction errors (RPEs), resembling temporal difference errors used in machine learning. However, recent studies describing slowly increasing dopamine signals have instead proposed that they represent state values and arise independent from somatic spiking activity. Here we developed experimental paradigms using virtual reality that disambiguate RPEs from values. We examined dopamine circuit activity at various stages, including somatic spiking, calcium signals at somata and axons, and striatal dopamine concentrations. Our results demonstrate that ramping dopamine signals are consistent with RPEs rather than value, and this ramping is observed at all stages examined. Ramping dopamine signals can be driven by a dynamic stimulus that indicates a gradual approach to a reward. We provide a unified computational understanding of rapid phasic and slowly ramping dopamine signals: dopamine neurons perform a derivative-like computation over values on a moment-by-moment basis.
Assuntos
Dopamina/metabolismo , Transdução de Sinais , Potenciais de Ação/fisiologia , Animais , Axônios/metabolismo , Cálcio/metabolismo , Sinalização do Cálcio , Corpo Celular/metabolismo , Sinais (Psicologia) , Neurônios Dopaminérgicos/fisiologia , Fluorometria , Masculino , Camundongos Endogâmicos C57BL , Modelos Neurológicos , Estimulação Luminosa , Recompensa , Sensação , Fatores de Tempo , Área Tegmentar Ventral/metabolismo , Realidade VirtualRESUMO
Sensory stimuli drive the maturation and function of the mammalian nervous system in part through the activation of gene expression networks that regulate synapse development and plasticity. These networks have primarily been studied in mice, and it is not known whether there are species- or clade-specific activity-regulated genes that control features of brain development and function. Here we use transcriptional profiling of human fetal brain cultures to identify an activity-dependent secreted factor, Osteocrin (OSTN), that is induced by membrane depolarization of human but not mouse neurons. We find that OSTN has been repurposed in primates through the evolutionary acquisition of DNA regulatory elements that bind the activity-regulated transcription factor MEF2. In addition, we demonstrate that OSTN is expressed in primate neocortex and restricts activity-dependent dendritic growth in human neurons. These findings suggest that, in response to sensory input, OSTN regulates features of neuronal structure and function that are unique to primates.
Assuntos
Evolução Molecular , Proteínas Musculares/metabolismo , Neocórtex/metabolismo , Neurônios/metabolismo , Fatores de Transcrição/metabolismo , Transcriptoma , Animais , Sequência de Bases , Osso e Ossos/metabolismo , Dendritos/metabolismo , Elementos Facilitadores Genéticos/genética , Feminino , Humanos , Fatores de Transcrição MEF2/metabolismo , Macaca mulatta , Masculino , Camundongos , Dados de Sequência Molecular , Proteínas Musculares/genética , Músculos/metabolismo , Neocórtex/citologia , Neurônios/citologia , Especificidade de Órgãos , Especificidade da Espécie , Fatores de Transcrição/genéticaRESUMO
Neuronal activity regulates the development and maturation of excitatory and inhibitory synapses in the mammalian brain. Several recent studies have identified signalling networks within neurons that control excitatory synapse development. However, less is known about the molecular mechanisms that regulate the activity-dependent development of GABA (gamma-aminobutyric acid)-releasing inhibitory synapses. Here we report the identification of a transcription factor, Npas4, that plays a role in the development of inhibitory synapses by regulating the expression of activity-dependent genes, which in turn control the number of GABA-releasing synapses that form on excitatory neurons. These findings demonstrate that the activity-dependent gene program regulates inhibitory synapse development, and suggest a new role for this program in controlling the homeostatic balance between synaptic excitation and inhibition.
Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Sinapses/metabolismo , Fatores de Transcrição/metabolismo , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Células Cultivadas , Eletrofisiologia , Regulação da Expressão Gênica , Hipocampo/citologia , Camundongos , Neurônios/metabolismo , Ratos , Fatores de Transcrição/genética , Transfecção , Ácido gama-Aminobutírico/metabolismoRESUMO
Understanding the role of the pulvinar nucleus may be critical for guiding circuit-targeted neurosurgical intervention in some patients. In this report, a 33-year-old female presented with focal onset occipital epilepsy with secondary generalization and with a previously radiated arteriovenous malformation within the right primary visual cortex. Phase II monitoring demonstrated the pulvinar nucleus was not involved in subclinical seizures restricted to the primary visual cortex, but it did become involved in clinical events with more extensive seizure spread into higher visual cortical regions. She underwent responsive neurostimulation (RNS) with implantation of leads within the primary visual cortex. This case demonstrates the late propagation of epileptic activity from the visual cortex to the pulvinar nucleus and illustrates the pulvinar nucleus' connections with higher-order visual areas.
RESUMO
The responsive neurostimulator system has become increasingly popular in the surgical management of refractory epilepsy, with targeting of various thalamic nuclei showing promising results in select patients. A 42-year-old female presented for evaluation of refractory epilepsy consisting of generalized tonic-clonic and focal seizures with preserved awareness. Phase I and II monitoring suggested multifocal bilateral epilepsy with bilateral frontal onset, and the patient underwent robot-guided bilateral centromedian thalamic placement of the RNS System. In this operative video, the authors share their institutional experience and protocol utilizing the ExcelsiusGPS robot in the placement of the RNS System in the thalamus. The video can be found here: https://stream.cadmore.media/r10.3171/2024.4.FOCVID243.
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BACKGROUND: Medical knowledge during the medieval ages flourished under the influence of great scholars of the Islamic Golden age such as Ibn Sina (Latinized as Avicenna), Abu Bakr al-Razi (Rhazes), and Abu al-Qasim Khalaf ibn al-Abbas al-Zahrawi, known as Albucasis. Much has been written on al-Zahrawi's innovation in various disciplines of medicine and surgery. In this article, we focus for on the contributions of al-Zahrawi toward the treatment of neurological disorders in the surgical chapters of his medical encyclopedia, Kitab al-Tasrif (The Method of Medicine). METHODS: Excerpts from a modern copy of volume 30 of al-Zahrawi's Kitab al-Tasrif were reviewed and translated by the primary author from Arabic to English, to further provide specific details regarding his neurosurgical knowledge. In addition, a literature search was performed using PubMed and Google Scholar to review prior reports on al-Zahrawi's neurosurgical instructions. RESULTS: In addition to what is described in the literature of al-Zahrawi's teachings in cranial and spine surgery, we provide insight into his diagnosis and management of cranial and spinal trauma, the devices he used, and prognostication of various traumatic injuries. CONCLUSIONS: Al-Zahrawi was a renowned physician during the Islamic Golden age who made significant contributions to the diagnosis and treatment of neurological conditions, particularly cranial and spinal cord injuries. He developed innovative surgical techniques for trephination and spinal traction, which are still used in modern neurosurgery. His insights make him worthy of recognition as an important figure in the history of neurological surgery.
Assuntos
Medicina Arábica , Doenças do Sistema Nervoso , Neurocirurgia , Traumatismos da Medula Espinal , Traumatismos da Coluna Vertebral , Humanos , Masculino , Doenças do Sistema Nervoso/cirurgia , Neurocirurgia/história , Procedimentos Neurocirúrgicos , Medicina Arábica/históriaRESUMO
To thrive in complex environments, animals and artificial agents must learn to act adaptively to maximize fitness and rewards. Such adaptive behavior can be learned through reinforcement learning1, a class of algorithms that has been successful at training artificial agents2-6 and at characterizing the firing of dopamine neurons in the midbrain7-9. In classical reinforcement learning, agents discount future rewards exponentially according to a single time scale, controlled by the discount factor. Here, we explore the presence of multiple timescales in biological reinforcement learning. We first show that reinforcement agents learning at a multitude of timescales possess distinct computational benefits. Next, we report that dopamine neurons in mice performing two behavioral tasks encode reward prediction error with a diversity of discount time constants. Our model explains the heterogeneity of temporal discounting in both cue-evoked transient responses and slower timescale fluctuations known as dopamine ramps. Crucially, the measured discount factor of individual neurons is correlated across the two tasks suggesting that it is a cell-specific property. Together, our results provide a new paradigm to understand functional heterogeneity in dopamine neurons, a mechanistic basis for the empirical observation that humans and animals use non-exponential discounts in many situations10-14, and open new avenues for the design of more efficient reinforcement learning algorithms.
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Importance: While variations in quality of care have been described between US regions, physician-level practice pattern variations within regions remain poorly understood, notably among specialists. Objective: To examine within-area physician-level variations in decision-making in common clinical scenarios where guidelines specifying appropriateness or quality of care exist. Design Setting and Participants: This cross-sectional study used 2016 through 2019 data from a large nationwide network of commercial insurers, provided by Health Intelligence Company, LLC, within 5 metropolitan statistical areas (MSAs). Physician-level variations in appropriateness and quality of care were measured using 14 common clinical scenarios involving 7 specialties. The measures were constructed using public quality measure definitions, clinical guidelines, and appropriateness criteria from the clinical literature. Physician performance was calculated using a multilevel model adjusted for patient age, sex, risk score, and socioeconomic status with physician random effects. Measure reliability for each physician was calculated using the signal-to-noise approach. Within-MSA variation was calculated between physician quintiles adjusted for patient attributes, with the first quintile denoting highest quality or appropriateness and the fifth quintile reflecting the opposite. Data were analyzed March through October 2021. Main Outcomes and Measures: Fourteen measures of quality or appropriateness of care, with 2 measures each in the domains of cardiology, endocrinology, gastroenterology, pulmonology, obstetrics, orthopedics, and neurosurgery. Results: A total of 8788 physicians were included across the 5 MSAs, and about 2.5 million unique patient-physician pairs were included in the measures. Within the 5 MSAs, on average, patients in the measures were 34.7 to 40.7 years old, 49.1% to 52.3% female, had a mean risk score of 0.8 to 1.0, and more likely to have an employer-sponsored insurance plan that was either self-insured or fully insured (59.8% to 97.6%). Within MSAs, physician-level variations were qualitatively similar across measures. For example, statin therapy in patients with coronary artery disease ranged from 54.3% to 70.9% in the first quintile of cardiologists to 30.5% to 42.6% in the fifth quintile. Upper endoscopy in patients with gastroesophageal reflux disease without alarm symptoms spanned 14.6% to 16.9% in the first quintile of gastroenterologists to 28.2% to 33.8% in the fifth quintile. Among patients with new knee or hip osteoarthritis, 2.1% to 3.4% received arthroscopy in the first quintile of orthopedic surgeons, whereas 25.5% to 30.7% did in the fifth quintile. Appropriate prenatal screening among pregnant patients ranged from 82.6% to 93.6% in the first quintile of obstetricians to 30.9% to 65.7% in the fifth quintile. Within MSAs, adjusted differences between quintiles approximated unadjusted differences. Measure reliability, which can reflect consistency and reproducibility, exceeded 70.0% across nearly all measures in all MSAs. Conclusions and Relevance: In this cross-sectional study of 5 US metropolitan areas, sizeable physician-level practice variations were found across common clinical scenarios and specialties. Understanding the sources of these variations may inform efforts to improve the value of care.
Assuntos
Endocrinologia , Médicos , Adulto , Estudos Transversais , Feminino , Humanos , Masculino , Padrões de Prática Médica , Reprodutibilidade dos TestesRESUMO
A 79-year-old man with coronary artery disease and tremor-predominant Parkinson's disease underwent a gross total resection of a high-grade glioma and exhibited what appeared to be polymorphic ventricular tachycardia lasting 15-20 seconds on postoperative day 1. Further evaluation revealed that the patient did not have ventricular tachycardia, and that his abnormal telemetry signals were instead an artifact of his Parkinson's tremor. This case underscores the importance of considering tremor artifact when evaluating abnormal telemetry and electrocardiogram signals in patients with tremor, and highlights some features that can distinguish tremor artifact from a true arrhythmia.
Assuntos
Eletrocardiografia , Doença de Parkinson/fisiopatologia , Complicações Pós-Operatórias/diagnóstico , Taquicardia Ventricular/diagnóstico , Telemetria , Tremor/diagnóstico , Idoso , Diagnóstico Diferencial , Reações Falso-Positivas , Humanos , Masculino , Tremor/fisiopatologiaRESUMO
OBJECTIVE: Neuromonitoring of primary motor regions allows preservation of motor strength and is frequently employed during cranial procedures. Less is known about protection of sensory function and ability to modulate movements, both of which rely on integrity of thalamocortical afferents (TCA) to fronto-parietal regions. We describe our experience with TCA monitoring and their cortical relays during brain tumor surgery. METHODOLOGY: To study its feasibility and usefulness, continuous somatosensory evoked potentials (SSEP) recording via a subdural electrode was attempted in 32 consecutive patients. RESULTS: Median and posterior tibial SSEP were successfully monitored in 31 and 17 patients respectively. SSEP improved lesion localization and prevented unnecessary cortical stimulation in 9 and 16 cases respectively. A threshold of ≥30% SSEP amplitude decrease influenced management in 10 patients while a decrement of ≥50 % had a sensitivity of 0.89 and specificity of 1 in detecting worsening of sensory function. Simultaneous motor evoked potentials (MEP) and SSEP monitoring were performed in 10 cases, 9 of which showed short-lived fluctuations of the former. CONCLUSION: Direct cortical SSEP monitoring is feasible, informs management and predicts outcome. SIGNIFICANCE: Early intervention prevents sensory deficit. Concomitant MEP fluctuations may reflect modulation of motor activity by TCA.
Assuntos
Neoplasias Encefálicas/cirurgia , Craniotomia/métodos , Potenciais Somatossensoriais Evocados/fisiologia , Monitorização Neurofisiológica Intraoperatória/métodos , Córtex Motor/fisiologia , Tálamo/fisiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias Encefálicas/fisiopatologia , Eletrocorticografia/métodos , Estudos de Viabilidade , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos RetrospectivosRESUMO
The development of biocompatible photopolymerizing polymers for biomedical and tissue engineering applications has the potential to reduce the invasiveness and cost of biomaterial implants designed to repair or augment tissues. However, more information is needed about the cellular toxicity of the compounds and initiators used in these systems. The current study evaluates the cellular toxicity of three ultraviolet sensitive photoinitiators on six different cell populations that are used for engineering numerous tissues. The photoinitiator 2-hydroxy-1-[4-(hydroxyethoxy)phenyl]-2-methyl-1-propanone (Irgacure 2959) caused minimal toxicity (cell death) over a broad range of mammalian cell types and species. It was also demonstrated that different cell types have variable responses to identical concentrations of the same photoinitiator. While inherent differences in the cell lines may contribute to the variable cytotoxicity, a correlation between cellular proliferation rate (population doubling time) and increased cytotoxicity of the photoinitiator was observed. Cell lines that divided more quickly were more sensitive to photoinitiator-induced cell death. In summary, the photoinitiator Irgacure 2959 is well tolerated by many cell types over a range of mammalian species. Cell photoencapsulation strategies may be optimized to improve cell survival by manipulating proliferation rate.
Assuntos
Materiais Biocompatíveis/farmacologia , Técnicas de Cultura de Células/métodos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Hidrogéis/química , Propano/análogos & derivados , Propano/farmacologia , Engenharia Tecidual/métodos , Materiais Biocompatíveis/efeitos da radiação , Linhagem Celular/efeitos dos fármacos , Linhagem Celular/fisiologia , Relação Dose-Resposta a Droga , Relação Dose-Resposta à Radiação , Hidrogéis/farmacologia , Hidrogéis/efeitos da radiação , Teste de Materiais , Fotoquímica/métodos , Transplante de Tecidos , Raios UltravioletaRESUMO
BACKGROUND: Neurogenic stress cardiomyopathy (NSC) is a known complication of aneurysmal subarachnoid hemorrhage (SAH). Detailed analyses of risk factors for its occurrence across large cohorts are relatively sparse. METHODS: A consecutive group of 300 patients with aneurysmal SAH was reviewed for the presence of markers of myocardial injury, including electrocardiogram changes (long QT, T-wave inversion), elevated plasma troponin levels (≥0.1), and echocardiogram findings (decreased ejection fraction and wall motion abnormalities). NSC was defined as the presence of at least 1 marker of myocardial injury. Univariate and multivariate analyses were conducted to assess the correlation of NSC and individual markers of myocardial injury with age, gender, medical comorbidities, medications, current smoking status, Hunt-Hess grade, and Fisher grade. Medical comorbidities were assessed based on reported medical history or reported use of comorbidity-specific medications at the time of presentation. RESULTS: Across the cohort, 27% of patients had a plasma troponin elevation of at least 0.1; 13%, a prolonged QT interval; 16%, new T-wave inversions; 18%, a depressed ejection fraction (<55%); and 15%, echocardiographic wall motion abnormalities. After a multivariate analysis, significant risk factors for NSC included higher Hunt-Hess grade on presentation (odds ratio [OR] = 2.33, P = 4.52 × 10(-6)), current smoking status (OR = 2.00, P = 0.030), and older age (OR = 1.03, P = 0.048). Hypertension was protective against NSC (OR = 0.48, P = 0.031). Patient gender, hyperlipidemia, diabetes, coronary artery disease, statin use, beta blocker use, angiotensin-converting enzyme inhibitor use, aspirin use, and thicker SAH (Fisher grade 3) were not significant risk factors for NSC. CONCLUSIONS: Higher Hunt-Hess grade, current smoking status, lack of hypertension, and older age were the strongest predictors of NSC.
Assuntos
Cardiomiopatias/etiologia , Estresse Fisiológico , Hemorragia Subaracnóidea/complicações , Adulto , Idoso , Cardiomiopatias/diagnóstico por imagem , Estudos de Coortes , Eletrocardiografia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Volume Sistólico , Resultado do Tratamento , Troponina I/sangue , UltrassonografiaRESUMO
Organismal development requires the precise coordination of genetic programs to regulate cell fate and function. MEF2 transcription factors (TFs) play essential roles in this process but how these broadly expressed factors contribute to the generation of specific cell types during development is poorly understood. Here we show that despite being expressed in virtually all mammalian tissues, in the retina MEF2D binds to retina-specific enhancers and controls photoreceptor cell development. MEF2D achieves specificity by cooperating with a retina-specific factor CRX, which recruits MEF2D away from canonical MEF2 binding sites and redirects it to retina-specific enhancers that lack the consensus MEF2-binding sequence. Once bound to retina-specific enhancers, MEF2D and CRX co-activate the expression of photoreceptor-specific genes that are critical for retinal function. These findings demonstrate that broadly expressed TFs acquire specific functions through competitive recruitment to enhancers by tissue-specific TFs and through selective activation of these enhancers to regulate tissue-specific genes.
Assuntos
Regulação da Expressão Gênica no Desenvolvimento/genética , Proteínas de Homeodomínio/metabolismo , Células Fotorreceptoras/fisiologia , Retina/citologia , Transativadores/metabolismo , Adaptação Ocular/genética , Fatores Etários , Animais , Animais Recém-Nascidos , Imunoprecipitação da Cromatina , Eletrorretinografia , Embrião de Mamíferos , Proteínas do Olho/metabolismo , Genoma , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Fatores de Transcrição MEF2/genética , Fatores de Transcrição MEF2/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mutação/genética , Retina/crescimento & desenvolvimentoRESUMO
Experience-dependent gene transcription is required for nervous system development and function. However, the DNA regulatory elements that control this program of gene expression are not well defined. Here we characterize the enhancers that function across the genome to mediate activity-dependent transcription in mouse cortical neurons. We find that the subset of enhancers enriched for monomethylation of histone H3 Lys4 (H3K4me1) and binding of the transcriptional coactivator CREBBP (also called CBP) that shows increased acetylation of histone H3 Lys27 (H3K27ac) after membrane depolarization of cortical neurons functions to regulate activity-dependent transcription. A subset of these enhancers appears to require binding of FOS, which was previously thought to bind primarily to promoters. These findings suggest that FOS functions at enhancers to control activity-dependent gene programs that are critical for nervous system function and provide a resource of functional cis-regulatory elements that may give insight into the genetic variants that contribute to brain development and disease.
Assuntos
Regulação da Expressão Gênica/genética , Neurônios/fisiologia , 2-Amino-5-fosfonovalerato/farmacologia , Animais , Proteína de Ligação a CREB/metabolismo , Embrião de Mamíferos , Antagonistas de Aminoácidos Excitatórios/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Estudo de Associação Genômica Ampla , Humanos , Histona Desmetilases com o Domínio Jumonji/metabolismo , Fatores de Transcrição MEF2/genética , Fatores de Transcrição MEF2/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Mutação/genética , Neurônios/efeitos dos fármacos , Proteínas Oncogênicas v-fos/metabolismo , Cloreto de Potássio/farmacologia , Bloqueadores dos Canais de Sódio/farmacologia , Tetrodotoxina/farmacologia , Fatores de Tempo , Córtex Visual/citologiaRESUMO
Despite significant heritability of autism spectrum disorders (ASDs), their extreme genetic heterogeneity has proven challenging for gene discovery. Studies of primarily simplex families have implicated de novo copy number changes and point mutations, but are not optimally designed to identify inherited risk alleles. We apply whole-exome sequencing (WES) to ASD families enriched for inherited causes due to consanguinity and find familial ASD associated with biallelic mutations in disease genes (AMT, PEX7, SYNE1, VPS13B, PAH, and POMGNT1). At least some of these genes show biallelic mutations in nonconsanguineous families as well. These mutations are often only partially disabling or present atypically, with patients lacking diagnostic features of the Mendelian disorders with which these genes are classically associated. Our study shows the utility of WES for identifying specific genetic conditions not clinically suspected and the importance of partial loss of gene function in ASDs.
Assuntos
Transtorno Autístico/diagnóstico , Transtorno Autístico/genética , Exoma/genética , Estudo de Associação Genômica Ampla/métodos , Adolescente , Animais , Células Cultivadas , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Humanos , Masculino , Linhagem , Ratos , Análise de Sequência de DNA/métodos , Adulto JovemRESUMO
EphB receptor tyrosine kinases control multiple steps in nervous system development. However, it remains unclear whether EphBs regulate these different developmental processes directly or indirectly. In addition, given that EphBs signal through multiple mechanisms, it has been challenging to define which signaling functions of EphBs regulate particular developmental events. To address these issues, we engineered triple knock-in mice in which the kinase activity of three neuronally expressed EphBs can be rapidly, reversibly and specifically blocked. We found that the tyrosine kinase activity of EphBs was required for axon guidance in vivo. In contrast, EphB-mediated synaptogenesis occurred normally when the kinase activity of EphBs was inhibited, suggesting that EphBs mediate synapse development by an EphB tyrosine kinase-independent mechanism. Taken together, our data indicate that EphBs control axon guidance and synaptogenesis by distinct mechanisms and provide a new mouse model for dissecting EphB function in development and disease.
Assuntos
Química Encefálica/genética , Encéfalo/embriologia , Encéfalo/fisiologia , Engenharia de Proteínas/métodos , Receptores da Família Eph/genética , Transdução de Sinais/fisiologia , Sequência de Aminoácidos , Animais , Química Encefálica/fisiologia , Células Cultivadas , Feminino , Técnicas de Introdução de Genes , Células HEK293 , Humanos , Camundongos , Camundongos da Linhagem 129 , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Dados de Sequência Molecular , Técnicas de Cultura de Órgãos , Gravidez , Ratos , Receptores da Família Eph/fisiologiaRESUMO
Charged multivesicular body protein 1A (CHMP1A; also known as chromatin-modifying protein 1A) is a member of the ESCRT-III (endosomal sorting complex required for transport-III) complex but is also suggested to localize to the nuclear matrix and regulate chromatin structure. Here, we show that loss-of-function mutations in human CHMP1A cause reduced cerebellar size (pontocerebellar hypoplasia) and reduced cerebral cortical size (microcephaly). CHMP1A-mutant cells show impaired proliferation, with increased expression of INK4A, a negative regulator of stem cell proliferation. Chromatin immunoprecipitation suggests loss of the normal INK4A repression by BMI in these cells. Morpholino-based knockdown of zebrafish chmp1a resulted in brain defects resembling those seen after bmi1a and bmi1b knockdown, which were partially rescued by INK4A ortholog knockdown, further supporting links between CHMP1A and BMI1-mediated regulation of INK4A. Our results suggest that CHMP1A serves as a critical link between cytoplasmic signals and BMI1-mediated chromatin modifications that regulate proliferation of central nervous system progenitor cells.