E. coli Toxin YjjJ (HipH) Is a Ser/Thr Protein Kinase That Impacts Cell Division, Carbon Metabolism, and Ribosome Assembly.

Protein Ser/Thr kinases are posttranslational regulators of key molecular processes in bacteria, such as cell division and antibiotic tolerance. Here, we characterize the E. coli toxin YjjJ (HipH), a putative protein kinase annotated as a member of the family of HipA-like Ser/Thr kinases, which are involved in antibiotic tolerance. Using SILAC-based phosphoproteomics we provide experimental evidence that YjjJ is a Ser/Thr protein kinase and its primary protein substrates are the ribosomal protein RpmE (L31) and the carbon storage regulator CsrA. YjjJ activity impacts ribosome assembly, cell division, and central carbon metabolism but it does not increase antibiotic tolerance as does its homologue HipA. Intriguingly, overproduction of YjjJ and its kinase-deficient variant can activate HipA and other kinases, pointing to a cross talk between Ser/Thr kinases in E. coli. IMPORTANCE Adaptation to growth condition is the key for bacterial survival, and protein phosphorylation is one of the strategies adopted to transduce extracellular signal in physiological response. In a previous work, we identified YjjJ, a putative kinase, as target of the persistence-related HipA kinase. Here, we performed the characterization of this putative kinase, complementing phenotypical analysis with SILAC-based phosphoproteomics and proteomics. We provide the first experimental evidence that YjjJ is a Ser/Thr protein kinase, having as primary protein substrates the ribosomal protein RpmE (L31) and the carbon storage regulator CsrA. We show that overproduction of YjjJ has a major influence on bacterial physiology, impacting DNA segregation, cell division, glycogen production, and ribosome assembly.

Compulsory and voluntary admissions in comparison: A 9-year long observational study.

BACKGROUND: Few studies, so far, have been specifically designed to highlight the features related to Compulsory Admissions (CA) and Voluntary Admissions (VA) in Italian psychiatric emergency wards. AIMS: The main purpose of this observational study was to compare the sociodemographic and clinical characteristics of VA and CA and to explore possible predictors of re-admissions. METHODS: During a 6-month Index Period (February, the 1st-July, the 31st 2008) all psychiatric admissions were documented and then followed-up through all available informatic systems for the next 9 years. RESULTS: Out of 390 hospitalizations, 101 (25.9%) were compulsory (CA rate was 2.79 per 10,000 inhabitants per year, mean duration of hospitalizations of 7.33 ± 7.84 days). Diagnoses were recorded for the 325 patients who had been hospitalized during index period: schizophrenic psychoses ([p = .042], in particular schizophrenia [p = .027]), manic episode (p = .044), and delusional disorders (p = .009) were associated with CA; conversely, the diagnosis of unipolar major depression (p = .005) and personality disorders (p = .048) were significantly more frequent in VA. The 325 admitted patients were followed up for 1,801 person-years. No significant differences were found in terms of drop-outs, transferring, and discharge rates, and mortality rates due to both natural causes and suicides. Factors associated with at least one compulsory readmission were younger age and having had a previous CA (p = .011); conversely having been engaged with psychiatric services for over 1 year prior to index hospitalization was protective for a subsequent CA (p = .013). CONCLUSIONS: After a 40-year old political reform, the current study shows that, in a context of integrated outpatient and inpatient services, engagement with outpatient care may be protective for compulsory rehospitalization.

Clinical Associations Between Severity of Impulsivity, Psychiatric Morbidity, Dysfunctional Defences and Personality Disorder: A Comparative Study With Axis-I Disorders.

OBJECTIVE: Psychiatric morbidity, impulsive behaviour and use of dysfunctional and maladaptive defences are core features of personality disorder (PD). This study aims to evaluate the significance of the strength of the association between these three core dimensions and PD. METHOD: Using a cross-sectional design, a sample of co-morbid Axis-I & -II disorders, and a sample of Axis-I disorders with no co-morbid PD were recruited at three general psychiatric mental health resource centres and then compared.PD as dependent variable was analysed both as a categorical and as a dimensional entity using the Structured Clinical Interview for DSM-IV. The Symptoms Checklist 90-R general severity index (GSI), the Barratt Impulsivity Scale (BIS) and the Defense Style Questionnaire (DSQ) were used to measure severity of psychiatric morbidity, impulsivity and defensive style, respectively. RESULTS: BIS was a highly significant predictor of categorical PD (ß = .13, SE = .03, p < .001), but not GSI and DSQ. BIS and GSI significantly predicted PD as a dimensional construct (ß = 0.32, SE = .08, t = 4.05, p < 0.001; and ß = 5.04, SE = 1.54, t = 3.28, p = 0.002, respectively). The diagnostic efficiency statistics found that BIS had greater sensitivity (.82) and specificity (.79), and overall predictive power (.87) of correctly identifying true positive and true negative PD diagnosis compared to the other two measures. CONCLUSIONS: BIS may be used in routine clinical practice as a screening measure to identify the presence of PD in complex presentations.

Loss of ELK1 has differential effects on age-dependent organ fibrosis.

ETS domain-containing protein-1 (ELK1) is a transcription factor important in regulating αvß6 integrin expression. αvß6 integrins activate the profibrotic cytokine Transforming Growth Factor ß1 (TGFß1) and are increased in the alveolar epithelium in idiopathic pulmonary fibrosis (IPF). IPF is a disease associated with aging and therefore we hypothesised that aged animals lacking Elk1 globally would develop spontaneous fibrosis in organs where αvß6 mediated TGFß activation has been implicated. Here we identify that Elk1-knockout (Elk1-/0) mice aged to one year developed spontaneous fibrosis in the absence of injury in both the lung and the liver but not in the heart or kidneys. The lungs of Elk1-/0 aged mice demonstrated increased collagen deposition, in particular collagen 3α1, located in small fibrotic foci and thickened alveolar walls. Despite the liver having relatively low global levels of ELK1 expression, Elk1-/0 animals developed hepatosteatosis and fibrosis. The loss of Elk1 also had differential effects on Itgb1, Itgb5 and Itgb6 expression in the four organs potentially explaining the phenotypic differences in these organs. To understand the potential causes of reduced ELK1 in human disease we exposed human lung epithelial cells and murine lung slices to cigarette smoke extract, which lead to reduced ELK1 expression andmay explain the loss of ELK1 in human disease. These data support a fundamental role for ELK1 in protecting against the development of progressive fibrosis via transcriptional regulation of beta integrin subunit genes, and demonstrate that loss of ELK1 can be caused by cigarette smoke.

Reduced Ets Domain-containing Protein Elk1 Promotes Pulmonary Fibrosis via Increased Integrin αvß6 Expression.

Idiopathic pulmonary fibrosis (IPF) is a progressive fibrotic lung disease with high mortality. Active TGFß1 is considered central to the pathogenesis of IPF. A major mechanism of TGFß1 activation in the lung involves the epithelially restricted αvß6 integrin. Expression of the αvß6 integrin is dramatically increased in IPF. How αvß6 integrin expression is regulated in the pulmonary epithelium is unknown. Here we identify a region in the ß6 subunit gene (ITGB6) promoter acting to markedly repress basal gene transcription, which responds to both the Ets domain-containing protein Elk1 (Elk1) and the glucocorticoid receptor (GR). Both Elk1 and GR can regulate αvß6 integrin expression in vitro We demonstrate Elk1 binding to the ITGB6 promoter basally and that manipulation of Elk1 or Elk1 binding alters ITGB6 promoter activity, gene transcription, and αvß6 integrin expression. Crucially, we find that loss of Elk1 causes enhanced Itgb6 expression and exaggerated lung fibrosis in an in vivo model of fibrosis, whereas the GR agonist dexamethasone inhibits Itgb6 expression. Moreover, Elk1 dysregulation is present in epithelium from patients with IPF. These data reveal a novel role for Elk1 regulating ITGB6 expression and highlight how dysregulation of Elk1 can contribute to human disease.

Insomnia and somnolence associated with second-generation antidepressants during the treatment of major depression: a meta-analysis.

BACKGROUND: Sleep reduction or enhancement is frequently observed with second-generation antidepressant treatments, and they can be beneficial or harmful depending on the symptom profile of each subject. Nevertheless, relatively little attention has been given so far to rank those effects across compounds. The aim of this meta-analysis is to provide quantitative data about short-term rates of insomnia and somnolence associated with 14 second-generation antidepressants during the treatment of major depression. METHODS: A literature search and a search of unpublished documents were performed. Eligible studies focusing on MD patients treated with second-generation antidepressants were entered in the analysis. Our primary outcome measures were insomnia and somnolence rates induced by antidepressants as compared with those associated with placebo. Sensitivity analyses were carried out as well. RESULTS: Ten second-generation antidepressants showed higher rates of insomnia than placebo. The highest incidence was found for bupropion and desvenlafaxine. Agomelatine was the only antidepressant with a lower likelihood of inducing insomnia than placebo. Eleven antidepressants were associated with higher rates of somnolence than placebo. Fluvoxamine and mirtazapine showed the highest frequency of somnolence. Bupropion induced somnolence to a lower extent than placebo. Sensitivity analyses showed a degree of variation of those findings. DISCUSSION: Antidepressants are associated with different insomnia and somnolence rates, mainly depending on their mechanisms of action. Despite some limitations, we underscore that the treatment-emergent insomnia and/or somnolence are frequent, and they could be used in clinical practice to face the specific needs of each patient.

The influence of AHI1 variants on the diagnosis and treatment outcome in schizophrenia.

The present study aimed to explore whether four single nucleotide polymorphisms (SNPs) within the AHI1 gene could be associated with schizophrenia (SCZ) and whether they could predict the clinical outcomes in SCZ patients treated with antipsychotics. Four hundred twenty-six (426) in-patients with SCZ and 345 controls were genotyped for four AHI1 SNPs (rs11154801, rs7750586, rs9647635 and rs9321501). Baseline and clinical measures for SCZ patients were assessed through the Positive and Negative Syndrome Scale (PANSS). Allelic and genotypic frequencies in SCZ subjects were compared with those of controls using the χ2 statistics. The repeated-measure ANOVA was used for the assessment of treatment outcomes measured by PANSS changes. The case-control analysis did not show any difference in the genotypic distribution of the SNPs, while in the allelic analysis, a weak association was found between the rs9647635 A allele and SCZ. Furthermore, in the haplotype analysis, three haplotypes resulted in being associated with SCZ. On the other hand, two SNPs (rs7750586 and rs9647635) were associated with clinical improvement of negative symptoms in the allelic analysis, although in the genotypic analysis, only trends of association were found for the same SNPs. Our findings suggest a possible influence of AHI1 variants on SCZ susceptibility and antipsychotic response, particularly concerning negative symptomatology. Subsequent well-designed studies would be mandatory to confirm our results due to the methodological shortcomings of the present study.

Abelson helper integration site-1 gene variants on major depressive disorder and bipolar disorder.

OBJECTIVE: The present study aimed to explore whether 4 single nucleotide polymorphisms (SNPs) within the AHI1 gene could be associated with major depressive disorder (MD) and bipolar disorder (BD), and whether they could predict clinical outcomes in mood disorders. METHODS: One hundred and eighty-four (184) patients with MD, 170 patients with BD and 170 healthy controls were genotyped for 4 AHI1 SNPs (rs11154801, rs7750586, rs9647635 and rs9321501). Baseline and final clinical measures for MD patients were assessed through the Hamilton Rating Scale for Depression (HAM-D). Allelic and genotypic frequencies in MD and BD subjects were compared with those of each disorder and healthy group using the χ(2) statistics. Repeated measures ANOVA was used to test possible influences of SNPs on treatment efficacy. RESULTS: The rs9647635 A/A was more represented in subjects with BD as compared with MD and healthy subjects together. The rs9647635 A/A was also more presented in patients with MD than in healthy subjects. With regard to the allelic analysis, rs9647635 A allele was more represented in subjects with BD compared with healthy subjects, while it was not observed between patients with MD and healthy subjects. CONCLUSION: Our findings provide potential evidence of an association between some variants of AHI1 and mood disorders susceptibility but not with clinical outcomes. However, we will need to do more adequately-powered and advanced association studies to draw any conclusion due to clear limitations.

Lack of influence of rs4680 (COMT) and rs6276 (DRD2) on diagnosis and clinical outcomes in patients with major depression.

OBJECTIVE: The gene coding for the catechol-O-methyltransferase (COMT) and the one coding for the dopamine receptor 2 (DRD2) have been linked with major depression (MD) and with the response to antidepressants in several studies. However, contrasting findings have been reported as well. The aim of the present study is, therefore, to investigate possible influences of rs4680 within COMT and rs6276 within DRD2, analyzed both individually and in combination, on the diagnosis and clinical outcomes in a sample of Korean MD patients treated with antidepressants. METHODS: Totally, 184 Korean in-patients suffering from MD treated with either paroxetine or venlafaxine and 220 healthy control subjects were included in the present study. Depression severity was assessed by means of the Hamilton Rating Scale for Depression. RESULTS: We were not able to find any association between the two variants under investigation and diagnosis of MD, as well as with antidepressant response. CONCLUSIONS: Although limited by several factors, including the small sample size and the impossibility to extend our findings to patients treated with different antidepressants, the results of our study provide support to the notion that these variants might not play a major role in the etiology and clinical outcomes of MD.

Trait-aggressiveness and impulsivity: role of psychological resilience and childhood trauma in a sample of male prisoners.

BACKGROUND: One of the major challenges for research in the field of human aggression is the need to define the role of personality and trait-like dimensions, such as impulsivity and aggressiveness, in predisposing to violent behavior. AIMS: 1) To determine whether trait- aggressiveness and impulsivity may be associated with socio-demographic, clinical and crime history variables in a sample of male prisoners; 2) to detect any association of those traits with measures of early traumatic experiences and current resilience traits. METHODS: A sample of male prisoners (n = 1356) underwent the Brown-Goodwin Assessment for Lifetime History of Aggression (BGLHA) and the Barratt Impulsivity Scale (BIS). Axis I psychiatric disorders were also assessed. Early traumatic experiences and psychological resilience were detected respectively by the Childhood Trauma Questionnaire (CTQ) and the Connor-Davidson Resilience Scale (CD-RISC). Two non-linear logistic regression models were performed to test for the best predictors of trait-aggressiveness and impulsivity. RESULTS: Subjects with a history of substance use disorders and self-mutilation reported both higher BGLHA and BIS scores. Axis I disorders and suicide attempts were associated with aggressiveness, but not to impulsivity. A consistent correlation was found between BGLHA scores and early traumatic experiences. Resilience was positively correlated to impulsivity but not to aggressiveness scores. CONCLUSIONS: Our results support the view that aggressiveness and impulsivity are two different, albeit related trait-like dimensions of personality, having a different relationship with resilience, and, inferentially, a different impact over the development of psychiatric disorders.

The 5-HTTLPR polymorphism and posttraumatic stress disorder: a meta-analysis.

Environmental and genetic factors contribute to the development of posttraumatic stress disorder (PTSD). Variation in the 5-HTTLPR polymorphism of the serotonin transporter gene has been hypothesized to affect risk for PTSD. With the aim of investigating this association, we conducted a meta-analysis to shed light on prior controversial results and increase statistical power to detect smaller effect sizes. PubMed and ISI databases were searched for studies published until December 2012. Twelve studies have been included, all based on trauma-exposed samples. Data were analyzed with Cochrane Collaboration Review Manager Software (Version 5). Quality and publication bias were assessed. Metaregressions were performed using Comprehensive Meta-Analysis software, Version 2. Taking into account all studies, no association was found between 5-HTTLPR and PTSD (p = .10), with evidence of between-study heterogeneity, which could be partly explained by gender differences. In sensitivity analyses, we found an association between SS genotype and PTSD in high trauma-exposed participants (p < .001). To be a carrier of the SS genotype seems to represent a risk factor for PTSD in high trauma exposure. Further studies focusing on Gene × Environment interactions are needed to better understand the role of this polymorphism in PTSD.

Social adjustment among treatment responder patients with mood disorders.

BACKGROUND: Patients with major depression (MD) show reduced social adjustment when compared with healthy controls. However, even among treatment responders, significant differences in social adjustment occur. The main aim of the present work is to study several socio-demographic and clinical variables possibly influencing social adjustment in MD patients who responded to treatment. METHODS: Two hundred and eleven MD patients experiencing a depressive episode who responded to their current treatment were recruited within the context of a large European multicentre project. Our primary outcome measure was the association between 19 socio-demographic and clinical variables and total social adjustment scores, as measured with the Social Adjustment Scale (SAS). Secondary outcome measures included the associations between the same variables and SAS sub-scales, and the associations between these variables and self-esteem, as measured with the Rosenberg Self-Esteem Scale. RESULTS: A co-morbidity with anxiety disorders and the severity of residual depression symptoms were the strongest independent factors associated with poorer social adjustment, in terms of total and most sub-areas' SAS scores. Other variables associated with total and sub-areas' SAS scores were identified as well, although some variations across different areas were observed. LIMITATIONS: The cross-sectional design, the retrospective assessment of data and the lack of a placebo control group. CONCLUSIONS: Our results confirm that a co-morbidity with anxiety disorders and higher residual depression symptoms could reduce social adjustment among responder MD patients. Further longitudinal studies are needed to confirm our results.

Association between Sirtuin 2 gene rs10410544 polymorphism and depression in Alzheimer's disease in two independent European samples.

Among the several genes associated with late-onset Alzheimer's disease (LOAD), recently, Sirtuin genes have roused a growing interest because of their involvement in metabolic homeostasis and in brain aging. Particularly SIRT2 gene has been associated with Alzheimer's disease (AD) as well as with mood disorders. The aim of this study is to investigate the possible associations between Sirtuin 2 gene (SIRT2) rs10410544 polymorphism and AD as well as depression in AD. In addition, we performed some exploratory analyses to investigate possible associations between the rs10410544 genotype and clinical features. We investigated these associations in two independent samples: the first one was composed of 275 Greek inhabitants and 117 patients; the second sample counted 181 Italian people and 43 patients. All patients were affected by LOAD. We failed to find any association between rs10410544 genotype and AD in the two samples. On the other hand, we found an association between the single nucleotide polymorphism (SNP) and depressive symptomatology (in the total sample p = 0.002), which was modulated by the tumor necrosis factor (TNF) values. Particularly, TT genotype seems to be protective versus depression. Finally, in the exploratory analyses, we found that the TT genotype was associated with earlier AD onset and a longer duration of the illness. In conclusion, we confirmed the association between SIRT2 gene and mood disturbances, although in AD patients. Further, we provided evidence that the TT genotype may be protective versus depressive symptoms, allowing an easier and thus earlier diagnosis of AD. This awareness may lead to a more detailed approach to these patients concerning diagnosis and therapy.

Loss of serum response factor in keratinocytes results in hyperproliferative skin disease in mice.

The transcription factor serum response factor (SRF) plays a crucial role in the development of several organs. However, its role in the skin has not been explored. Here, we show that keratinocytes in normal human and mouse skin expressed high levels of SRF but that SRF expression was strongly downregulated in the hyperproliferative epidermis of wounded and psoriatic skin. Keratinocyte-specific deletion within the mouse SRF locus during embryonic development caused edema and skin blistering, and all animals died in utero. Postnatal loss of mouse SRF in keratinocytes resulted in the development of psoriasis-like skin lesions. These lesions were characterized by inflammation, hyperproliferation, and abnormal differentiation of keratinocytes as well as by disruption of the actin cytoskeleton. Ultrastructural analysis revealed markedly reduced cell-cell and cell-matrix contacts and loss of cell compaction in all epidermal layers. siRNA-mediated knockdown of SRF in primary human keratinocytes revealed that the cytoskeletal abnormalities and adhesion defects were a direct consequence of the loss of SRF. In contrast, the hyperproliferation observed in vivo was an indirect effect that was most likely a consequence of the inflammation. These results reveal that loss of SRF disrupts epidermal homeostasis and strongly suggest its involvement in the pathogenesis of hyperproliferative skin diseases, including psoriasis.

Severe intestinal obstruction on induced smooth muscle-specific ablation of the transcription factor SRF in adult mice.

BACKGROUND & AIMS: SRF (Serum Response Factor), a widely expressed transcription factor, controls expression of mitogen-responsive and muscle-specific genes, thereby regulating the contractile actin microfilament. Genetic Srf deletion studies showed SRF to be indispensable for in vivo skeletal and cardiac muscle cell development. We now investigated for the first time in vivo SRF functions in smooth muscle cells of adult mice. METHODS: We conditionally deleted a floxed Srf allele (Srf(flex1)) in adult mice by inducible activation of the CreER(T2) recombinase expressed specifically in smooth muscle cells. Tamoxifen-induced CreER(T2) activity stimulated deletion of exon 1 coding sequences of Srf(flex1), thereby abolishing full-length SRF protein expression in adult smooth muscle cells of the analyzed organs: colon, bladder, and stomach. RESULTS: Smooth muscle cell-specific ablation of full-length SRF protein in adult mice showed impaired contraction of intestinal smooth muscle, resulting in defective peristalsis. Mutant mice died within 2 weeks of tamoxifen treatment, displaying clear symptoms of ileus paralyticus. Cultured primary SRF-deficient colon smooth muscle cells were viable, but displayed drastic structural alterations and elevated senescence, paralleled by degeneration of the actin microfilament and impaired expression of smooth muscle-specific genes. CONCLUSIONS: SRF plays a vital role in the contractile activity and cytoskeletal architecture of adult smooth muscle cells and is therefore essential for physiologic functions of the gastrointestinal tract in vivo. Our mouse genetic model may resemble features of human chronic intestinal pseudo-obstruction.

Serum response factor contributes selectively to lymphocyte development.

Serum response factor (SRF), is a crucial transcription factor for murine embryonic development and for the function of muscle cells and neurons. Gene expression data show that SRF and its transcriptional cofactors are also expressed in lymphocyte precursors and mature lymphocytes. However, the role of SRF in lymphocyte development has not been addressed in vivo so far, attributed in part to early embryonic lethality of conventional Srf-null mice. To determine the in vivo role of SRF in developing lymphocytes, we specifically inactivated the murine Srf gene during T or B cell development using lymphocyte-specific Cre transgenic mouse lines. T cell-specific Srf deletion led to a severe block in thymocyte development at the transition from CD4/CD8 double to single positive stage. The few residual T cells detectable in the periphery retained at least one functional Srf allele, thereby demonstrating the importance of SRF in T cell development. In contrast, deletion of Srf in developing B cells did not interfere with the growth and survival of B cells in general, yet led to a complete loss of marginal zone B cells and a marked reduction of the CD5+ B cell subset. Our study also revealed a contribution of SRF to the expression of the surface molecules IgM, CD19, and the chemokine receptor 4 in B lymphocytes. We conclude that SRF fulfills essential and distinct functions in the differentiation of different types of lymphocytes.

Induction of the lac promoter in the absence of DNA loops and the stoichiometry of induction.

In vivo induction of the Escherichia coli lactose operon as a function of inducer concentration generates a sigmoidal curve, indicating a non-linear response. Suggested explanations for this dependence include a 2:1 inducer-repressor stoichiometry of induction, which is the currently accepted view. It is, however, known for decades that, in vitro, operator binding as a function of inducer concentration is not sigmoidal. This discrepancy between in vivo and in vitro data has so far not been resolved. We demonstrate that the in vivo non-linearity of induction is due to cooperative repression of the wild-type lac operon through DNA loop formation. In the absence of DNA loops, in vivo induction curves are hyperbolic. In the light of this result, we re-address the question of functional molecular inducer-repressor stoichiometry in induction of the lac operon.

Serum response factor controls neuronal circuit assembly in the hippocampus.

Higher organisms rely on multiple modes of memory storage using the hippocampal network, which is built by precisely orchestrated mechanisms of axonal outgrowth, guidance and synaptic targeting. We demonstrate essential roles of the transcription factor serum response factor (SRF), a sensor of cytoskeletal actin dynamics, in all these processes. Conditional deletion of the mouse Srf gene reduced neurite outgrowth and abolished mossy fiber segregation, resulting in ectopic fiber growth inside the pyramidal layer. SRF-deficient mossy fibers aberrantly targeted CA3 somata for synapse formation. Axon guidance assays showed that SRF was a key mediator of ephrin-A and semaphorin guidance cues; in SRF-deficient neurons, these resulted in the formation of F-actin-microtubule rings rather than complete growth cone collapse. Dominant-negative variants of the SRF cofactor megakaryocytic acute leukemia (MAL) severely impeded neurite outgrowth and guidance. These data highlight essential links between SRF-mediated transcription and axon guidance and circuit formation in the hippocampus.

Neuronal migration in the murine rostral migratory stream requires serum response factor.

The central nervous system is fundamentally dependent on guided cell migration, both during development and in adulthood. We report an absolute requirement of the transcription factor serum response factor (SRF) for neuronal migration in the mouse forebrain. Conditional, late-prenatal deletion of Srf causes neurons to accumulate ectopically at the subventricular zone (SVZ), a prime neurogenic region in the brain. SRF-deficient cells of the SVZ exhibit impaired tangential chain migration along the rostral migratory stream into the olfactory bulb. SVZ explants display retarded chain migration in vitro. Regarding target genes, SRF deficiency impairs expression of the beta-actin and gelsolin genes, accompanied by reduced cytoskeletal actin fiber density. At the posttranslational level, cofilin, a key regulator of actin dynamics, displays dramatically elevated inhibitory phosphorylation at Ser-3. Our studies indicate that SRF-controlled gene expression directs both the structure and dynamics of the actin microfilament, thereby determining cell-autonomous neuronal migration.