Drosophila Fezf coordinates laminar-specific connectivity through cell-intrinsic and cell-extrinsic mechanisms

Laminar arrangement of neural connections is a fundamental feature of neural circuit organization. Identifying mechanisms that coordinate neural connections within correct layers is thus vital for understanding how neural circuits are assembled. In the medulla of the Drosophila visual system neurons form connections within ten parallel layers. The M3 layer receives input from two neuron types that sequentially innervate M3 during development. Here we show that M3-specific innervation by both neurons is coordinated by Drosophila Fezf (dFezf), a conserved transcription factor that is selectively expressed by the earlier targeting input neuron. In this cell, dFezf instructs layer specificity and activates the expression of a secreted molecule (Netrin) that regulates the layer specificity of the other input neuron. We propose that employment of transcriptional modules that cell-intrinsically target neurons to specific layers, and cell-extrinsically recruit other neurons is a general mechanism for building layered networks of neural connections.

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AAV11 permits efficient retrograde targeting of projection neurons

10.1101/2022.01.13.476170 ◽

2022 ◽

Author(s):

Zengpeng Han ◽

Nengsong Luo ◽

Jiaxin Kou ◽

Lei Li ◽

Wenyu Ma ◽

...

Keyword(s):

Neural Circuits ◽

Neural Circuit ◽

Brain Area ◽

Brain Diseases ◽

Projection Neurons ◽

Recording Technology ◽

Neural Connections ◽

Host Immune Responses ◽

Promising Tool ◽

High Level

Viral tracers that permit efficient retrograde targeting of projection neurons are powerful vehicles for structural and functional dissections of the neural circuit and for the treatment of brain diseases. Recombinant adeno-associated viruses (rAAVs) are the most potential candidates because they are low-toxic with high-level transgene expression and minimal host immune responses. Currently, some rAAVs based on capsid engineering for retrograde tracing have been widely used in the analysis and manipulation of neural circuits, but suffer from brain area selectivity and inefficient retrograde transduction in certain neural connections. Here, we discovered that the recombinant adeno-associated virus 11 (rAAV11) exhibits potent retrograde labeling of projection neurons with enhanced efficiency to rAAV2-retro in some neural connections. Combined with calcium recording technology, rAAV11 can be used to monitor neuronal activities by expressing Cre recombinase or calcium-sensitive functional probe. In addition, we further showed the suitability of rAAV11 for astrocyte targeting. These properties make rAAV11 a promising tool for the mapping and manipulation of neural circuits and gene therapy of some neurological and neurodegenerative disorders.

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Hunchback activates Bicoid in post-mitotic Pair1 neurons to regulate synapse number

10.1101/2021.11.29.470460 ◽

2021 ◽

Author(s):

Kristen M Lee ◽

Amanda M Linskens ◽

Chris Q Doe

Keyword(s):

Transcription Factor ◽

Transcription Factors ◽

Neural Circuits ◽

Neural Circuit ◽

Anatomical Location ◽

Mature Neuron ◽

Synapse Density ◽

And Function ◽

And Behavior ◽

Homeodomain Transcription Factors

The proper formation and function of neural circuits is crucial for cognition, sensation, and behavior. Neural circuits are highly-specific, and this specificity is dependent on neurons developing key features of their individual identities: morphology, anatomical location, molecular expression and biophysiological properties. Previous research has demonstrated that a neurons identity is, in part, generated by the temporal transcription window the neuron is born in, and the homeodomain transcription factors expressed in the mature neuron. However, whether temporal transcription factors and homeodomain transcription factors regulate neural circuit formation, maintenance and function remains unknown. Here, we utilize a well-characterized neural circuit in the Drosophila larvae, the Pair1 neuron. We determined that in the Pair1 neuron, the temporal transcription factor Hunchback activates the homeodomain transcription factor Bicoid (Bcd). Both Hunchback and Bcd are expressed in Pair1 throughout larval development. Interestingly, Hunchback and Bcd were not required in Pair1 for neurotransmitter identity or axonal morphology, but were required for synapse density. We found that these transcription factors were functioning post-mitotically in Pair1 to regulate synapse density. Additionally, knocking down Hunchback and Bcd in Pair1 neurons disrupted the behavioral output of the circuit. We utilized the genetic tool TransTango to determine that Hunchback function in Pair1 is to repress forming synapses with erroneous neurons. To our knowledge, these data are the first to show Hunchback activating Bcd expression, as well as the first to demonstrate a role for Hunchback and Bcd post-mitotically.

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Use of a Neural Circuit Probe to Validate in silico Predictions of Inhibitory Connections

10.1101/204594 ◽

2017 ◽

Cited By ~ 1

Author(s):

Honglei Liu ◽

Daniel Bridges ◽

Connor Randall ◽

Sara A. Solla ◽

Bian Wu ◽

...

Keyword(s):

In Silico ◽

Neural Circuits ◽

Neural Circuit ◽

Interventional Procedure ◽

Spike Trains ◽

Local Network ◽

Electrode Arrays ◽

Neural Connections ◽

Neural Spike ◽

Statistical Relationships

AbstractUnderstanding how neuronal signals propagate in local network is an important step in understanding information processing. As a result, spike trains recorded with Multi-electrode Arrays (MEAs) have been widely used to study behaviors of neural connections. Studying the dynamics of neuronal networks requires the identification of both excitatory and inhibitory connections. The detection of excitatory relationships can robustly be inferred by characterizing the statistical relationships of neural spike trains. However, the identification of inhibitory relationships is more difficult: distinguishing endogenous low firing rates from active inhibition is not obvious. In this paper, we propose an in silico interventional procedure that makes predictions about the effect of stimulating or inhibiting single neurons on other neurons, and thereby gives the ability to accurately identify inhibitory causal relationships. To experimentally test these predictions, we have developed a Neural Circuit Probe (NCP) that delivers drugs transiently and reversibly on individually identified neurons to assess their contributions to the neural circuit behavior. With the help of NCP, three inhibitory connections identified by our in silico modeling were validated through real interventional experiments. Together, these methods provide a basis for mapping complete neural circuits.

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BRN2 is a non-canonical melanoma tumor-suppressor

Nature Communications ◽

10.1038/s41467-021-23973-5 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Michael Hamm ◽

Pierre Sohier ◽

Valérie Petit ◽

Jérémy H. Raymond ◽

Véronique Delmas ◽

...

Keyword(s):

Transcription Factor ◽

Transcription Factors ◽

Tumor Suppressor ◽

The Other ◽

Pi3k Signaling ◽

Melanoma Tumor ◽

Temporal Regulation ◽

Metastatic Colonization ◽

Pou Domain

AbstractWhile the major drivers of melanoma initiation, including activation of NRAS/BRAF and loss of PTEN or CDKN2A, have been identified, the role of key transcription factors that impose altered transcriptional states in response to deregulated signaling is not well understood. The POU domain transcription factor BRN2 is a key regulator of melanoma invasion, yet its role in melanoma initiation remains unknown. Here, in a BrafV600EPtenF/+ context, we show that BRN2 haplo-insufficiency promotes melanoma initiation and metastasis. However, metastatic colonization is less efficient in the absence of Brn2. Mechanistically, BRN2 directly induces PTEN expression and in consequence represses PI3K signaling. Moreover, MITF, a BRN2 target, represses PTEN transcription. Collectively, our results suggest that on a PTEN heterozygous background somatic deletion of one BRN2 allele and temporal regulation of the other allele elicits melanoma initiation and progression.

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A Genetic Screen of the Drosophila X Chromosome for Mutations That Modify Deformed Function

Genetics ◽

10.1093/genetics/150.4.1497 ◽

1998 ◽

Vol 150 (4) ◽

pp. 1497-1511 ◽

Cited By ~ 1

Author(s):

Brian Florence ◽

William McGinnis

Keyword(s):

Transcription Factor ◽

Transcriptional Regulation ◽

Cell Signaling ◽

X Chromosome ◽

Adaptor Protein ◽

Genetic Screen ◽

The Other ◽

Homeotic Gene ◽

Hox Proteins ◽

Hox Gene

Abstract We have screened the Drosophila X chromosome for genes whose dosage affects the function of the homeotic gene Deformed. One of these genes, extradenticle, encodes a homeodomain transcription factor that heterodimerizes with Deformed and other homeotic Hox proteins. Mutations in the nejire gene, which encodes a transcriptional adaptor protein belonging to the CBP/p300 family, also interact with Deformed. The other previously characterized gene identified as a Deformed interactor is Notch, which encodes a transmembrane receptor. These three genes underscore the importance of transcriptional regulation and cell-cell signaling in Hox function. Four novel genes were also identified in the screen. One of these, rancor, is required for appropriate embryonic expression of Deformed and another homeotic gene, labial. Both Notch and nejire affect the function of another Hox gene, Ultrabithorax, indicating they may be required for homeotic activity in general.

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Whole-Genome Analysis of Genes Regulated by the Bacillus subtilis Competence Transcription Factor ComK

Journal of Bacteriology ◽

10.1128/jb.184.9.2344-2351.2002 ◽

2002 ◽

Vol 184 (9) ◽

pp. 2344-2351 ◽

Cited By ~ 110

Author(s):

Mitsuo Ogura ◽

Hirotake Yamaguchi ◽

Kazuo Kobayashi ◽

Naotake Ogasawara ◽

Yasutaro Fujita ◽

...

Keyword(s):

Transcription Factor ◽

Bacillus Subtilis ◽

Genetic Transformation ◽

Dna Microarray ◽

Genome Analysis ◽

Transformation Efficiency ◽

The Other ◽

Whole Genome ◽

Whole Genome Analysis ◽

Microarray Technique

ABSTRACT The Bacillus subtilis competence transcription factor ComK is required for establishment of competence for genetic transformation. In an attempt to study the ComK factor further, we explored the genes regulated by ComK using the DNA microarray technique. In addition to the genes known to be dependent on ComK for expression, we found many genes or operons whose ComK dependence was not known previously. Among these genes, we confirmed the ComK dependence of 16 genes by using lacZ fusions, and three genes were partially dependent on ComK. Transformation efficiency was significantly reduced in an smf disruption mutant, although disruption of the other ComK-dependent genes did not result in significant decreases in transformation efficiency. Nucleotide sequences similar to that of the ComK box were found for most of the newly discovered genes regulated by ComK.

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Oscillatory integration windows in neurons

10.1101/081471 ◽

2016 ◽

Author(s):

Nitin Gupta ◽

Swikriti Saran Singh ◽

Mark Stopfer

Keyword(s):

Neural Circuits ◽

Neural Circuit ◽

Field Potential ◽

Coincidence Detection ◽

Uniform Structure ◽

Detection Mechanism ◽

Oscillation Frequencies ◽

Local Field Potential Lfp ◽

Oscillatory Cycle

AbstractOscillatory synchrony among neurons occurs in many species and brain areas, and has been proposed to help neural circuits process information. One hypothesis states that oscillatory input creates cyclic integration windows: specific times in each oscillatory cycle when postsynaptic neurons become especially responsive to inputs. With paired local field potential (LFP) and intracellular recordings and controlled stimulus manipulations we directly tested this idea in the locust olfactory system. We found that inputs arriving in Kenyon cells (KCs) sum most effectively in a preferred window of the oscillation cycle. With a computational model, we found that the non-uniform structure of noise in the membrane potential helps mediate this process. Further experiments performed in vivo demonstrated that integration windows can form in the absence of inhibition and at a broad range of oscillation frequencies. Our results reveal how a fundamental coincidence-detection mechanism in a neural circuit functions to decode temporally organized spiking.

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Prominent Inhibitory Projections Guide Sensorimotor Computation: An Invertebrate Perspective

10.20944/preprints201908.0112.v1 ◽

2019 ◽

Author(s):

Samantha Hughes ◽

Tansu Celikel

Keyword(s):

Motor Neurons ◽

Neural Circuits ◽

Neural Circuit ◽

Sensory Information ◽

Circuit Complexity ◽

Inhibitory Circuits ◽

Invertebrate Species ◽

Gating Mechanism ◽

Motor Actions ◽

Sensorimotor Representations

From single-cell organisms to complex neural networks, all evolved to provide control solutions to generate context and goal-specific actions. Neural circuits performing sensorimotor computation to drive navigation employ inhibitory control as a gating mechanism, as they hierarchically transform (multi)sensory information into motor actions. Here, we focus on this literature to critically discuss the proposition that prominent inhibitory projections form sensorimotor circuits. After reviewing the neural circuits of navigation across various invertebrate species, we argue that with increased neural circuit complexity and the emergence of parallel computations inhibitory circuits acquire new functions. The contribution of inhibitory neurotransmission for navigation goes beyond shaping the communication that drives motor neurons, instead, include encoding of emergent sensorimotor representations. A mechanistic understanding of the neural circuits performing sensorimotor computations in invertebrates will unravel the minimum circuit requirements driving adaptive navigation.

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Contributions of UP Elements and the Transcription Factor FIS to Expression from the Seven rrn P1 Promoters inEscherichia coli

Journal of Bacteriology ◽

10.1128/jb.183.21.6305-6314.2001 ◽

2001 ◽

Vol 183 (21) ◽

pp. 6305-6314 ◽

Cited By ~ 88

Author(s):

Christine A. Hirvonen ◽

Wilma Ross ◽

Christopher E. Wozniak ◽

Erin Marasco ◽

Jennifer R. Anthony ◽

...

Keyword(s):

Transcription Factor ◽

Binding Sites ◽

Promoter Activity ◽

The Other ◽

Multigene Families ◽

Inescherichia Coli ◽

Start Site ◽

Transcription Start ◽

Control Of Gene Expression ◽

Up Elements

ABSTRACT The high activity of the rrnB P1 promoter inEscherichia coli results from acis-acting DNA sequence, the UP element, and atrans-acting transcription factor, FIS. In this study, we examine the effects of FIS and the UP element at the other sixrrn P1 promoters. We find that UP elements are present at all of the rrn P1 promoters, but they make different relative contributions to promoter activity. Similarly, FIS binds upstream of, and activates, all seven rrn P1 promoters but to different extents. The total number of FIS binding sites, as well as their positions relative to the transcription start site, differ at each rrn P1 promoter. Surprisingly, the FIS sites upstream of site I play a much larger role in transcription from most rrn P1 promoters compared to rrnBP1. Our studies indicate that the overall activities of the sevenrrn P1 promoters are similar, and the same contributors are responsible for these high activities, but these inputs make different relative contributions and may act through slightly different mechanisms at each promoter. These studies have implications for the control of gene expression of unlinked multigene families.

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