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Neuronal activity is crucial for adaptive circuit remodelling but poses an inherent risk to the stability of the genome across the long lifespan of postmitotic neurons1–5. Whether neurons have acquired specialized genome protection mechanisms that enable them to withstand decades of potentially damaging stimuli during periods of heightened activity is unknown. Here we identify an activity-dependent DNA repair mechanism in which a new form of the NuA4–TIP60 chromatin modifier assembles in activated neurons around the inducible, neuronal-specific transcription factor NPAS4. We purify this complex from the brain and demonstrate its functions in eliciting activity-dependent changes to neuronal transcriptomes and circuitry. By characterizing the landscape of activity-induced DNA double-strand breaks in the brain, we show that NPAS4–NuA4 binds to recurrently damaged regulatory elements and recruits additional DNA repair machinery to stimulate their repair. Gene regulatory elements bound by NPAS4–NuA4 are partially protected against age-dependent accumulation of somatic mutations. Impaired NPAS4–NuA4 signalling leads to a cascade of cellular defects, including dysregulated activity-dependent transcriptional responses, loss of control over neuronal inhibition and genome instability, which all culminate to reduce organismal lifespan. In addition, mutations in several components of the NuA4 complex are reported to lead to neurodevelopmental and autism spectrum disorders. Together, these findings identify a neuronal-specific complex that couples neuronal activity directly to genome preservation, the disruption of which may contribute to developmental disorders, neurodegeneration and ageing.

Neuronal activity-dependent gene expression is essential for brain development. Although transcriptional and epigenetic effects of neuronal activity have been explored in mice, such an investigation is lacking in humans. Because alterations in GABAergic neuronal circuits are implicated in neurological disorders, we conducted a comprehensive activity-dependent transcriptional and epigenetic profiling of human induced pluripotent stem cell-derived GABAergic neurons similar to those of the early developing striatum. We identified genes whose expression is inducible after membrane depolarization, some of which have specifically evolved in primates and/or are associated with neurological diseases, including schizophrenia and autism spectrum disorder (ASD). We define the genome-wide profile of human neuronal activity-dependent enhancers, promoters and the transcription factors CREB and CRTC1. We found significant heritability enrichment for ASD in the inducible promoters. Our results suggest that sequence variation within activity-inducible promoters of developing human forebrain GABAergic neurons contributes to ASD risk. Boulting et al. profile activity-dependent gene expression and regulatory elements in human induced pluripotent stem cell-derived GABAergic neurons and uncover a possible role for calcium-responsive gene promoters of these neurons in autism risk.

Behavioural experiences activate the FOS transcription factor in sparse populations of neurons that are critical for encoding and recalling specific events1–3. However, there is limited understanding of the mechanisms by which experience drives circuit reorganization to establish a network of Fos-activated cells. It is also not known whether FOS is required in this process beyond serving as a marker of recent neural activity and, if so, which of its many gene targets underlie circuit reorganization. Here we demonstrate that when mice engage in spatial exploration of novel environments, perisomatic inhibition of Fos-activated hippocampal CA1 pyramidal neurons by parvalbumin-expressing interneurons is enhanced, whereas perisomatic inhibition by cholecystokinin-expressing interneurons is weakened. This bidirectional modulation of inhibition is abolished when the function of the FOS transcription factor complex is disrupted. Single-cell RNA-sequencing, ribosome-associated mRNA profiling and chromatin analyses, combined with electrophysiology, reveal that FOS activates the transcription of Scg2, a gene that encodes multiple distinct neuropeptides, to coordinate these changes in inhibition. As parvalbumin- and cholecystokinin-expressing interneurons mediate distinct features of pyramidal cell activity4–6, the SCG2-dependent reorganization of inhibitory synaptic input might be predicted to affect network function in vivo. Consistent with this prediction, hippocampal gamma rhythms and pyramidal cell coupling to theta phase are significantly altered in the absence of Scg2. These findings reveal an instructive role for FOS and SCG2 in establishing a network of Fos-activated neurons via the rewiring of local inhibition to form a selectively modulated state. The opposing plasticity mechanisms acting on distinct inhibitory pathways may support the consolidation of memories over time. Novel experiences in mice lead to opposing effects on inhibition of Fos-activated hippocampal CA1 pyramidal neurons by parvalbumin- and cholecystokinin-expressing interneurons, revealing the roles of FOS and SCG2 in neural plasticity and consolidation of memories.

The interplay of transcription factors and cis -regulatory elements (CREs) orchestrates the dynamic and diverse genetic programs that assemble the human central nervous system (CNS) during development and maintain its function throughout life. Genetic variation within CREs plays a central role in phenotypic variation in complex traits including the risk of developing disease. We took advantage of the retina, a well-characterized region of the CNS known to be affected by pathogenic variants in CREs, to establish a roadmap for characterizing regulatory variation in the human CNS. This comprehensive analysis of tissue-specific regulatory elements, transcription factor binding, and gene expression programs in three regions of the human visual system (retina, macula, and retinal pigment epithelium/choroid) reveals features of regulatory element evolution that shape tissue-specific gene expression programs and defines regulatory elements with the potential to contribute to Mendelian and complex disorders of human vision.

SUMMARYOur understanding of the human brain is limited by the lack of experimental models to mechanistically probe the properties of brain cells at different developmental stages under normal and pathological conditions. We developed a new method for generating human cortico-striatal organoids from stem cell-derived single neural rosettes (SNRs) and used it to investigate cortico-striatal development and deficits caused by the deficiency of an autism- and intellectual disability-associated geneSHANK3. We show that SNR-derived organoids consist of different cortico-striatal cells, including pallial and subpallial progenitors, primary cortical and striatal neurons, interneurons, as well as macroglial and mural cells. We also demonstrate that neurons in SNR-derived organoids are predictably organized, functionally mature, and capable of establishing functional neural networks. Interestingly, we found that the cellular and electrophysiological deficits in SHANK3-deficient SNR-derived organoids are dependent on the level of SHANK3 expression and that organoids with complete hemizygousSHANK3deletion have disrupted expression of several clustered protocadherins and multiple primate-specific zinc-finger genes. Together, this study describes a new method for using SNRs to generate organoids, provides new insights into the cell lineages associated with human cortico-striatal development, and identifies specific molecular pathways disrupted by hemizygousSHANK3deletion, which is the most common genetic abnormality detected in patients with 22q13 deletion syndrome.

The interplay of transcription factors and cis-regulatory elements (CREs) orchestrates the dynamic and diverse genetic programs that assemble the human central nervous system (CNS) during development and maintain its function throughout life. Genetic variation within CREs plays a central role in phenotypic variation in complex traits including the risk of developing disease. We took advantage of the retina, a well-characterized region of the CNS known to be affected by pathogenic variants in CREs, to establish a roadmap for characterizing regulatory variation in the human CNS. This comprehensive analysis of tissue-specific regulatory elements, transcription factor binding, and gene expression programs in three regions of the human visual system (retina, macula, and retinal pigment epithelium/choroid) reveals features of regulatory element evolution that shape tissue-specific gene expression programs and defines regulatory elements with the potential to contribute to Mendelian and complex disorders of human vision.

Cis-regulatory elements (CREs) orchestrate the dynamic and diverse transcriptional programs that assemble the human central nervous system (CNS) during development and maintain its function throughout life. Genetic variation within CREs plays a central role in phenotypic variation in complex traits including the risk of developing disease. However, the cellular complexity of the human brain has largely precluded the identification of functional regulatory variation within the human CNS. We took advantage of the retina, a well-characterized region of the CNS with reduced cellular heterogeneity, to establish a roadmap for characterizing regulatory variation in the human CNS. This comprehensive resource of tissue-specific regulatory elements, transcription factor binding, and gene expression programs in three regions of the human visual system (retina, macula, retinal pigment epithelium/choroid) reveals features of regulatory element evolution that shape tissue-specific gene expression programs and defines the regulatory elements with the potential to contribute to mendelian and complex disorders of human vision.

Rett syndrome is caused by mutation of the MECP2 gene that codes for a protein that binds methylated DNA; this study reveals that MeCP2 affects the expression of long genes, which often serve neuronal functions. Autism-related Rett syndrome is caused by disruption of the MECP2 gene, which codes for a methyl-DNA binding protein, but how MECP2 may control transcription of other genes has remained unclear. Now Michael Greenberg and colleagues show that disruption of the Mecp2 gene in a mouse model and in human Rett syndrome leads to preferential upregulation of longer genes, and that these often serve neuronal functions. Further data indicate that decreasing the expression of long genes, via hypomethylation of the dinucleotide CA, attenuates Rett-related dysfunctions in cultured neurons lacking MECP2. Disruption of the MECP2 gene leads to Rett syndrome (RTT), a severe neurological disorder with features of autism1. MECP2 encodes a methyl-DNA-binding protein2 that has been proposed to function as a transcriptional repressor, but despite numerous mouse studies examining neuronal gene expression in Mecp2 mutants, no clear model has emerged for how MeCP2 protein regulates transcription3,4,5,6,7,8,9. Here we identify a genome-wide length-dependent increase in gene expression in MeCP2 mutant mouse models and human RTT brains. We present evidence that MeCP2 represses gene expression by binding to methylated CA sites within long genes, and that in neurons lacking MeCP2, decreasing the expression of long genes attenuates RTT-associated cellular deficits. In addition, we find that long genes as a population are enriched for neuronal functions and selectively expressed in the brain. These findings suggest that mutations in MeCP2 may cause neurological dysfunction by specifically disrupting long gene expression in the brain.

Enhancer elements are regulatory sequences within genomes that direct the selective expression of genes so that genetically identical cells can differentiate and acquire the highly specialized forms and functions required to build a functioning animal. To differentiate, cells must select from among the ~106 enhancers encoded in the genome the thousands of enhancers that drive the gene programs that impart their distinct features. We used a genetic approach to identify transcription factors (TFs) required for enhancer selection in fibroblasts. This revealed that the broadly expressed, growth factor-inducible TFs Fos/Jun (AP-1) play a central role in enhancer selection. Fos/Jun selects enhancers together with cell type-specific TFs by collaboratively binding to nucleosomal enhancers and directing recruitment of the SWI/SNF (BAF) chromatin remodeling complex to establish accessible chromatin. These experiments demonstrate how environmental signals acting via Fos/Jun and BAF coordinate with cell type-specific TFs to select enhancer repertoires that enable differentiation during development.

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.

Summary Sensory experience influences the establishment of neural connectivity through molecular mechanisms that remain unclear. Here, we employ single-nucleus RNA sequencing to investigate the contribution of sensory-driven gene expression to synaptic refinement in the dorsal lateral geniculate nucleus of the thalamus, a region of the brain that processes visual information. We find that visual experience induces the expression of the cytokine receptor Fn14 in excitatory thalamocortical neurons. By combining electrophysiological and structural techniques, we show that Fn14 is dispensable for early phases of refinement mediated by spontaneous activity but that Fn14 is essential for refinement during a later, experience-dependent period of development. Refinement deficits in mice lacking Fn14 are associated with functionally weaker and structurally smaller retinogeniculate inputs, indicating that Fn14 mediates both functional and anatomical rearrangements in response to sensory experience. These findings identify Fn14 as a molecular link between sensory-driven gene expression and vision-sensitive refinement in the brain.

We used genome-wide sequencing methods to study stimulus-dependent enhancer function in mouse cortical neurons. We identified approximately 12,000 neuronal activity-regulated enhancers that are bound by the general transcriptional co-activator CBP in an activity-dependent manner. A function of CBP at enhancers may be to recruit RNA polymerase II (RNAPII), as we also observed activity-regulated RNAPII binding to thousands of enhancers. Notably, RNAPII at enhancers transcribes bi-directionally a novel class of enhancer RNAs (eRNAs) within enhancer domains defined by the presence of histone H3 monomethylated at lysine 4. The level of eRNA expression at neuronal enhancers positively correlates with the level of messenger RNA synthesis at nearby genes, suggesting that eRNA synthesis occurs specifically at enhancers that are actively engaged in promoting mRNA synthesis. These findings reveal that a widespread mechanism of enhancer activation involves RNAPII binding and eRNA synthesis.

SummaryAlthough many transcription factors are known to control important aspects of neural development, the genome-wide programs that are directly regulated by these factors are not known. We have characterized the genetic program that is activated by MEF2, a key regulator of activity-dependent synapse development. These MEF2 target genes have diverse functions at synapses, revealing a broad role for MEF2 in synapse development. Several of the MEF2 targets are mutated in human neurological disorders including epilepsy and autism spectrum disorders, suggesting that these disorders may be caused by disruption of an activity-dependent gene program that controls synapse development. Our analyses also reveal that neuronal activity promotes alternative polyadenylation site usage at many of the MEF2 target genes, leading to the production of truncated mRNAs that may have different functions than their full-length counterparts. Taken together, these analyses suggest that the ubiquitously expressed transcription factor MEF2 regulates an intricate transcriptional program in neurons that controls synapse development.

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. Osteocrin is a non-neuronal secreted protein in mice that has been evolutionarily repurposed to act as a neuronal development factor in primates. Much of the research on the gene expression networks that drive brain development has been performed in mice. Relatively little is known about how expression networks in other animal groups—particularly primates, in which the cerebral cortex is expanded—might differ from the mouse model. Here, Michael Greenberg and colleagues identify a non-neuronal secreted factor in mice, Osteocrin, that may have been re-purposed evolutionarily as a neuronal development gene in primates. Osteocrin is specifically expressed in the neocortex of the humans and macaques. In mice it is enriched in bone and muscle tissues, but not in the brain.

Bipolar disorder (BD) is a prevalent and severe mood disorder characterized by recurrent episodes of mania and depression. Both genetic and environmental factors have been implicated in BD etiology, but the biological underpinnings remain elusive. Recent genome-wide association studies (GWAS) for identifying genes conferring risk for schizophrenia, BD, and major depression, identified an association between single-nucleotide polymorphisms (SNPs) in the SYNE1 gene and increased risk of BD. SYNE1 has also been identified as a risk locus for multiple other neurological or neuromuscular genetic disorders. The BD associated SNPs map within the gene region homologous to part of rat Syne1 encompassing the brain specific transcripts encoding CPG2, a postsynaptic neuronal protein localized to excitatory synapses and an important regulator of glutamate receptor internalization. Here, we use RNA-seq, ChIP-seq and RACE to map the human SYNE1 transcriptome, focusing on the CPG2 locus. We validate several CPG2 transcripts, including ones not previously annotated in public databases, and identify and clone a full-length CPG2 cDNA expressed in human neocortex, hippocampus and striatum. Using lenti-viral gene knock down/replacement and surface receptor internalization assays, we demonstrate that human CPG2 protein localizes to dendritic spines in rat hippocampal neurons and is functionally equivalent to rat CPG2 in regulating glutamate receptor internalization. This study provides a valuable gene-mapping framework for relating multiple genetic disease loci in SYNE1 with their transcripts, and for evaluating the effects of missense SNPs identified by patient genome sequencing on neuronal function.

Inhibitory neurons regulate the adaptation of neural circuits to sensory experience, but the molecular mechanisms by which experience controls the connectivity between different types of inhibitory neuron to regulate cortical plasticity are largely unknown. Here we show that exposure of dark-housed mice to light induces a gene program in cortical vasoactive intestinal peptide (VIP)-expressing neurons that is markedly distinct from that induced in excitatory neurons and other subtypes of inhibitory neuron. We identify Igf1 as one of several activity-regulated genes that are specific to VIP neurons, and demonstrate that IGF1 functions cell-autonomously in VIP neurons to increase inhibitory synaptic input onto these neurons. Our findings further suggest that in cortical VIP neurons, experience-dependent gene transcription regulates visual acuity by activating the expression of IGF1, thus promoting the inhibition of disinhibitory neurons and affecting inhibition onto cortical pyramidal neurons.

mRNA synthesis, processing, and destruction involve a complex series of molecular steps that are incompletely understood. Because the RNA intermediates in each of these steps have finite lifetimes, extensive mechanistic and dynamical information is encoded in total cellular RNA. Here we report the development of SnapShot-Seq, a set of computational methods that allow the determination of in vivo rates of pre-mRNA synthesis, splicing, intron degradation, and mRNA decay from a single RNA-Seq snapshot of total cellular RNA. SnapShot-Seq can detect in vivo changes in the rates of specific steps of splicing, and it provides genome-wide estimates of pre-mRNA synthesis rates comparable to those obtained via labeling of newly synthesized RNA. We used SnapShot-Seq to investigate the origins of the intrinsic bimodality of metazoan gene expression levels, and our results suggest that this bimodality is partly due to spillover of transcriptional activation from highly expressed genes to their poorly expressed neighbors. SnapShot-Seq dramatically expands the information obtainable from a standard RNA-Seq experiment.

SummaryThe nervous system adapts to experience by inducing a transcriptional program that controls important aspects of synaptic plasticity. Although the molecular mechanisms of experience-dependent plasticity are well characterized in excitatory neurons, the mechanisms that regulate this process in inhibitory neurons are only poorly understood. Here, we describe a transcriptional program that is induced by neuronal activity in inhibitory neurons. We find that, while neuronal activity induces expression of early-response transcription factors such as Npas4 in both excitatory and inhibitory neurons, Npas4 activates distinct programs of late-response genes in inhibitory and excitatory neurons. These late-response genes differentially regulate synaptic input to these two types of neurons, promoting inhibition onto excitatory neurons while inducing excitation onto inhibitory neurons. These findings suggest that the functional outcomes of activity-induced transcriptional responses are adapted in a cell-type-specific manner to achieve a circuit-wide homeostatic response.

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, POMGNT1), some implicated for the first time in ASD. 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.

A differential equation in l for hydrogenic radial dipole matrix elements is generated from the recursion relations of Infeld and Hull [Rev. Mod. Phys. 23, 31 (1951)]. The equation is valid for all (n,n')\ensuremath{\gg}1, for all \ensuremath{\Vert}\ensuremath{\Delta}n\ensuremath{\Vert}ieq\ensuremath{\Vert}n'-n\ensuremath{\Vert}, and for bound-free transitions from excited states. Approximate solutions are obtained for the case l\ensuremath{\ll}n and are found to be equivalent to those of other workers when \ensuremath{\Vert}\ensuremath{\Delta}n\ensuremath{\Vert}\ensuremath{\gg}1. We also present a power-series solution in l good for all \ensuremath{\Vert}\ensuremath{\Delta}n\ensuremath{\Vert}. General features of the dependence of the matrix elements on l are explained.

Two entangled two-level system (or qubits) is the fundamental ‘brick’ in the construcion of quantum logic gates, which are the base of quantum networks. Quantum entanglement is also at the core of the duality principle relating fringe visibility and acquisition of which way information in a two-ways interferometer. We present here a quantum logic gate — the Symmetric Quanton-Detecton System, for which each qubit can play the role of quanton or which-way detector. Applying the results of Englert [Phys. Rev. Lett. 77, 2154 (1996).] we derive a pair of coupled duality relations for the system.

We introduce a measure Q of the "quality" of a quantum which-way detector, which characterizes its intrinsic ability to extract which-way information in an asymmetric two-way interferometer. The "quality" Q allows one to separate the contribution to the distinguishability of the ways arising from the quantum properties of the detector from the contribution stemming from a-priori which-way knowledge available to the experimenter, which can be quantified by a predictability parameter P. We provide an inequality relating these two sources of which-way information to the value of the fringe visibility displayed by the interferometer. We show that this inequality is an expression of duality, allowing one to trace the loss of coherence to the two reservoirs of which-way information represented by Q and P. Finally, we illustrate the formalism with the use of a quantum logic gate: the Symmetric Quanton-Detecton System (SQDS). The SQDS can be regarded as two qubits trying to acquire which way information about each other. The SQDS will provide an illustrating example of the reciprocal effects induced by duality between system and which-way detector., Comment: 10 pages, 5 figures

Explorations of the classical phase space for ion collisions with circular Rydberg atoms are presented. Intermediate-energy capture and ionization processes are studied through the numerical integration of Newton's equations of motion and through the graphical depiction of the outcomes of large numbers of trajectories. Maps which correlate initial conditions with final outcomes are used to identify zones of parameter space leading to Thomas capture, direct capture, binary-encounter ionization, saddle-point ionization, and ionization by S superpromotion (E. A. Solov'ev, Zh. Eksp. Teor. Fiz. 81, 1681 (1981) [Sov. Phys. JETP 54, 893 (1981)]). Charge-transfer channels in which the electron passes once or three times through the midplane between the nuclei are shown to occur in separate zones of parameter space over the entire range of projectile speeds above the mean velocity of the target electron.

Recent experimental measurements of charge transfer in ion collisions with circular-state Rydberg atoms (for which [ital m]=[ital l]=[ital n][minus]1) can be qualitatively reproduced using an elementary atomic model consisting of a classical electron in a circular orbit with an arbitrary axis of rotation defined by experiment. Contributions to capture are further separated into one-swap and three-swap charge transfers, revealing the relative importance of a Thomaslike mechanism for charge transfer at ion velocities of 1.00, 1.65, and 2.00 times the velocity of the target electron. The model is extended to estimate charge-transfer cross sections for ions incident on elliptic-state Rydberg atoms of specific eccentricity.

The physics of a Rydberg atom in a uniform dc electric field is a solvable problem [1]. The theory underlying this assertion has several components, which in turn rely on certain approximations, but the machinery as a whole has been put to the experimental test and found to be accurate to a level of up to 10 ppm [2]. The broad assumptions that allow one to investigate atoms, ions, and perhaps even molecules with some success are made in the spirit of multichannel quantum-defect theory (MQDT) [3, 4]. Such a treatment is appropriate to Rydberg systems, wherein one electron is significantly more excited than any of the others. The finer structural aspects of the atom + field system—as reflected in the detailed features of an observable spectrum—are associated with the highly excited electron only. The thrust of the present approach is to obtain a complete description of an excited hydrogen atom in an electric field, and to consider modifications to the atomic spectrum introduced by the presence of a nonhydrogenic atom’s core.

We thank P Braun (preceding Comment, Phys. Rev. A 46, 6108 (1992)) for clarifying how errors can arise in attempting to use the differential equation beyond its region of applicability. The principal results of our paper are correct for their stated domains.

Bell and Seaton's ab initio theory of dielectronic recombination is extended to include the influence of arbitrary electric fields in the $S$ matrix. Rydberg series of resonances are treated in quantum-defect-Stark theory. The zero-field rate of an $n$, $m$ manifold is enhanced up to a factor $\frac{({\ensuremath{\Gamma}}_{R}+{\ensuremath{\Gamma}}_{A})}{(\frac{{\ensuremath{\Gamma}}_{R}+{\ensuremath{\Gamma}}_{A}}{n})}$ as seen in a simple model. Previously ignored interference effects reduce the enhancement for interacting manifolds.

Theoretical photoabsorption cross sections for alkali-metal atoms in a static electric field $F$ are derived for energies near the zero-field ionization threshold ($\ensuremath{\epsilon}=0$), extending a previous development for hydrogen. Spectra result from zero-field dipole matrix elements and a density-of-states matrix ${D}_{{l}^{\ensuremath{'}}l}^{F}$. The factors ${D}_{{l}^{\ensuremath{'}}l}^{F}={({〈{\ensuremath{\Psi}}^{\ensuremath{'}}|\ensuremath{\Psi}〉}^{\ensuremath{-}1})}_{{l}^{\ensuremath{'}}l}$ represent a renormalization of the photoelectron's wave function ${\ensuremath{\Psi}}_{l}$ necessitated by the long-range Coulomb plus Stark potential. The matrix ${D}^{F}$ contains all spectral information on quasidiscrete Stark levels and continuum resonances, expressed as an algebraic function of (1) quantum defects ${\ensuremath{\mu}}_{l}$ embodying core effects, (2) a frame transformation between spherical and parabolic coordinates in the pure Coulomb field outside the alkali-metal core, and (3) factors ${H}_{{l}^{\ensuremath{'}}l}^{F}$ and ${h}_{{l}^{\ensuremath{'}}l}^{F}$ calculated from asymptotic amplitudes and phases of hydrogen-Stark wave functions of the parabolic dissociation channels. Hydrogenic parameters are calculated semianalytically within the WKB approximation; ${\ensuremath{\mu}}_{l}$ and dipole matrix elements are known independently. Predicted cross sections for photoionization of the excited $3^{2}P_{\frac{3}{2}}$ state of Na agree with experiment. The theory reproduces (a) asymmetric resonances observed at $\ensuremath{\epsilon}l0$, parametrized as a Beutler-Fano profile for a simple case, and (b) the oscillations observed at $\ensuremath{\epsilon}g0$, attenuated by factors $cos2\ensuremath{\pi}{\ensuremath{\mu}}_{l}$ from their predicted depth in H. Dependences on light polarization are sorted out for two-photon excitation.

A modified WKB treatment of a hydrogenic atom in a static electric field $F$ is found accurate over all energies $\ensuremath{\epsilon}$ to within 1% for $F\ensuremath{\le}5000$ kV/cm. This semianalytical technique describes the two properties of the wave function most relevant to photoionization and scattering: (1) the ratio of amplitudes at large and small distances ${A}_{{n}_{1}m}(\ensuremath{\epsilon},F)$, and (2) the asymptotic phase shift ${\ensuremath{\delta}}_{{n}_{1}m}(\ensuremath{\epsilon},F)$. The photoionization cross section from the ground state, given as a semianalytical function of $\ensuremath{\epsilon}$ and of the quantum numbers $m$ and ${n}_{1}$, describes the polarization-dependent shape resonances observed above the zero-field ionization threshold ($\ensuremath{\epsilon}=0$) and agrees with the exact calculations of Luc-Koenig and Bachelier. Complex-contour integration of WKB phase integrals reveals an equipartition of phase between the two sides of the potential barrier formed by the Coulomb and Stark fields. The total phase shift increases by $2\ensuremath{\pi}$ (not $\ensuremath{\pi}$) between successive quasistationary levels of constant ${n}_{1},m,F$. The WKB method originally applied to the Stark effect by Lanczos and generalized by Miller and Good is reviewed in an appendix.

Photoionization spectra of alkali atoms in a dc electric field are calculated semianalytically and agree with experiment. Cross sections depend on two distinct sets of parameters: (a) zero-field dipole matrix elements and quantum defects and (b) eigenfunctions of the external Coulomb-Stark potential. The field's effect on photoionization is condensed into a density-of-states matrix ${〈{\ensuremath{\Psi}}^{\ensuremath{'}}|\ensuremath{\Psi}〉}^{\ensuremath{-}1}$, whose use may be appropriate to long-range effects in all spectral phenomena.

SummaryOrganismal 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.

SummaryAutism spectrum disorders such as Rett syndrome (RTT) have been hypothesized to arise from defects in experience-dependent synapse maturation. RTT is caused by mutations in MECP2, a nuclear protein that becomes phosphorylated at S421 in response to neuronal activation. We show here that disruption of MeCP2 S421 phosphorylation in vivo results in defects in synapse development and behavior, implicating activity-dependent regulation of MeCP2 in brain development and RTT. We investigated the mechanism by which S421 phosphorylation regulates MeCP2 function and show by chromatin immunoprecipitation-sequencing that this modification occurs on MeCP2 bound across the genome. The phosphorylation of MeCP2 S421 appears not to regulate the expression of specific genes; rather, MeCP2 functions as a histone-like factor whose phosphorylation may facilitate a genome-wide response of chromatin to neuronal activity during nervous system development. We propose that RTT results in part from a loss of this experience-dependent chromatin remodeling.

Diverse semianalytical constructions of wave functions, approximate or exact, are combined through the introduction of novel concepts. These include representing wave functions by a mosaic of analytic functions of a phase variable phi, each of them adapted to the problem's features over a restricted range of a coordinate x, and focusing the numerical effort on the metric relation between phi and x. This shift of attention from the wave function proper to metric relations is viewed as the essence of the Milne approach and of its WKB approximation. Illustrative examples are worked out and discussed.

Asymmetric resonance profiles observed in H atoms in a strong electric field are derived analytically. The most significant deviations from a Lorentzian line shape, H/sup F/ = ..gamma../(scre/sup 2/+..gamma../sup 2/), occur for resonances near the top of a potential barrier. Parametrization as a Fano profile is inappropriate. The line-shape formula, a Lorentzian with energy-dependent reduced width ..gamma../sub Q/(scre) = ln(1+Q(1-Q)/sup -1-s/cre)/ln(( 1-Q)/sup -1/), depends on a single asymmetry parameter Q (0