scholarly journals The Hunchback temporal transcription factor determines motor neuron axon and dendrite targeting in Drosophila

2019 ◽  
Author(s):  
Austin Q. Seroka ◽  
Chris Q. Doe
Keyword(s):  
Transcription Factor ◽  
Motor Neurons ◽  
Neuronal Diversity ◽  
Molecular Identity ◽  
Extrinsic Cues ◽  
Circuit Development ◽  
Temporal Identity ◽  
Morphological Differences ◽  
And Behavior ◽  
Circuit Formation

AbstractThe generation of neuronal diversity is essential for circuit formation and behavior. Morphological differences in sequentially born neurons could be due to intrinsic molecular identity specified by temporal transcription factors (henceforth called intrinsic temporal identity) or due to changing extrinsic cues. Here we use the Drosophila NB7-1 lineage to address this question. NB7-1 sequentially generates the U1-U5 motor neurons; each has a distinct intrinsic temporal identity due to inheritance of a different temporal transcription factor at time of birth. Here we show that the U1-U5 neurons project axons sequentially, followed by sequential dendrite extension. We misexpress the earliest temporal transcription factor, Hunchback, to create “ectopic” U1 neurons with an early intrinsic temporal identity but later birth-order. These ectopic U1 neurons have axon muscle targeting and dendrite neuropil targeting consistent with U1 intrinsic temporal identity, rather than their time of birth or differentiation. We conclude that intrinsic temporal identity plays a major role in establishing both motor axon muscle targeting and dendritic arbor targeting, which are required for proper motor circuit development.

scholarly journals A novel temporal identity window generates alternating cardinal motor neuron subtypes in a single progenitor lineage

2020 ◽  
Author(s):  
Austin Seroka ◽  
Rita M Yazejian ◽  
Sen-Lin Lai ◽  
Chris Q Doe
Keyword(s):  
Transcription Factor ◽  
Motor Neuron ◽  
Motor Neurons ◽  
Target Selection ◽  
Oblique Muscle ◽  
Spatial Patterning ◽  
Temporal Patterning ◽  
Neuron Morphology ◽  
Temporal Identity ◽  
Necessary And Sufficient

AbstractSpatial patterning specifies neural progenitor identity, with further diversity generated by temporal patterning within individual progenitor lineages. These mechanisms generate cardinal classes of motor neurons (sharing a transcription factor identity and common muscle group targets). In Drosophila, two cardinal classes are Even-skipped (Eve)+ motor neurons projecting to dorsal muscles and Nkx6+ motor neurons projecting to ventral muscles. The Drosophila neuroblast 7-1 (NB7-1) lineage generates distinct Eve+ motor neurons via the temporal transcription factor (TTF) cascade Hunchback (Hb)-Krüppel (Kr)-Pdm-Castor (Cas). Here we show that a newly discovered Kr/Pdm temporal identity window gives rise to an Nkx6+ Eve-motor neuron projecting to ventral oblique muscles, resulting in alternation of cardinal motor neuron subtypes from a single progenitor (Eve>Nkx6>Eve). We show that co-overexpression of Kr/Pdm generates ectopic VO motor neurons within the NB7-1 lineage and that Kr/Pdm act via Nkx6, which itself is necessary and sufficient for VO motor neuron identity. Lastly, Nkx6 is required for ventral oblique muscle targeting, thereby linking temporal patterning to motor neuron morphology and synaptic target selection. In conclusion, we show that one neuroblast lineage generates interleaved cardinal motor neurons fates; that the Kr/Pdm TTFs form a novel temporal identity window that promotes expression of Nkx6; and that the Kr/Pdm>Nkx6 pathway is necessary and sufficient to specify VO motor neuron identity and morphology.

scholarly journals The role of lineage, hemilineage and temporal identity in establishing neuronal connectivity in the Drosophila larval CNS

2019 ◽  
Author(s):  
Brandon Mark ◽  
Sen-Lin Lai ◽  
Aref Arzan Zarin ◽  
Laurina Manning ◽  
Albert Cardona ◽  
...  
Keyword(s):  
Sensory Processing ◽  
Neural Circuit ◽  
Neuronal Morphology ◽  
Neural Progenitors ◽  
Neuronal Diversity ◽  
Developmental Mechanism ◽  
Temporal Identity ◽  
Circuit Formation ◽  
Synapse Targeting

AbstractThe mechanisms specifying neuronal diversity are well-characterized, yet it remains unclear how or if these mechanisms regulate neuronal morphology and connectivity. Here we map the developmental origin of 78 bilateral pairs of interneurons from seven identified neural progenitors (neuroblasts) within a complete TEM reconstruction of the Drosophila newly-hatched larval CNS. This allows us to correlate developmental mechanism with neuronal projections, synapse targeting, and connectivity. We find that clonally-related neurons from project widely in the neuropil, without preferential circuit formation. In contrast, the two NotchON/NotchOFF hemilineages from each neuroblast project to either dorsal motor neuropil (NotchON) or ventral sensory neuropil (NotchOFF). Thus, each neuroblast contributes both motor and sensory processing neurons. Lineage-specific constitutive Notch transforms sensory to motor hemilineages, showing hemilineage identity determines neuronal targeting. Within a hemilineage, temporal cohorts target processes and synapses to different sub-domains of the neuropil, effectively “tiling” the hemilineage neuropil, and hemilineage/temporal cohorts are enriched for shared connectivity. Thus, neuroblast lineage, hemilineage, and temporal identity progressively restrict neuropil targeting, synapse localization, and connectivity. We propose that mechanisms generating neural diversity are also determinants of neural circuit formation.

scholarly journals A novel temporal identity window generates alternating cardinal motor neuron subtypes in a single progenitor lineage

2020 ◽  
Author(s):  
Austin Q Seroka ◽  
Rita M Yazejian ◽  
Sen-Lin Lai ◽  
Chris Q Doe
Keyword(s):  
Transcription Factor ◽  
Motor Neuron ◽  
Motor Neurons ◽  
Target Selection ◽  
Oblique Muscle ◽  
Birth Date ◽  
Loss Of Function ◽  
Temporal Patterning ◽  
Temporal Identity ◽  
Necessary And Sufficient

Abstract Background: Spatial patterning specifies neural progenitor identity, with further diversity generated by temporal patterning within individual progenitor lineages. These mechanisms generate cardinal classes of motor neurons, sharing a transcription factor identity and common muscle group targets). In Drosophila , two cardinal classes are Even-skipped (Eve)+ motor neurons projecting to dorsal longitudinal muscles and Nkx6+ motor neurons projecting to ventral oblique muscles. The Drosophila neuroblast 7-1 (NB7-1) lineage generates distinct Eve+ motor neurons via the temporal transcription factor (TTF) cascade Hunchback (Hb)-Krüppel (Kr)-Pdm-Castor (Cas). Methods: Here we use sparse labelling and molecular markers to identify a novel VO motor neuron subtype in the NB7-1 lineage, and birth-date this neuron to a Kr+ Pdm+ temporal identity window. We selectively drive overexpression of Kr and Pdm in the NB7-1 lineage, and assay the production and axonal targeting of ectopic VO neurons. We then use gain- and loss-of-function strategies to show that the identity and targeting specificity of the VO neuron is dependent on the transcription factor Nkx6. Results: Here we show that a newly discovered Kr/Pdm temporal identity window gives rise to an Nkx6+ Eve- motor neuron projecting to ventral oblique muscles, resulting in alternation of cardinal motor neuron subtypes from a single progenitor (Eve>Nkx6>Eve). We show that co-overexpression of Kr/Pdm generates ectopic VO motor neurons within the NB7-1 lineage – the first evidence that this TTF combination specifies neuronal identity. Moreover, we show that the Kr/Pdm combination promotes Nkx6 expression, which itself is necessary and sufficient for ventral oblique muscle targeting, thereby linking temporal patterning to motor neuron synaptic target selection. Conclusions: We show that one neuroblast lineage generates interleaved cardinal motor neurons fates; that the Kr/Pdm TTFs form a novel temporal identity window that promotes expression of Nkx6; and that the Kr/Pdm>Nkx6 pathway is necessary and sufficient to specify VO motor neuron identity and morphology.

scholarly journals A developmental framework linking neurogenesis and circuit formation in the Drosophila CNS

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Brandon Mark ◽  
Sen-Lin Lai ◽  
Aref Arzan Zarin ◽  
Laurina Manning ◽  
Heather Q Pollington ◽  
...  
Keyword(s):  
Nervous System ◽  
Neural Circuit ◽  
Neural Progenitors ◽  
Dependent Manner ◽  
Neuronal Diversity ◽  
Synaptic Targeting ◽  
Connectivity Structure ◽  
Temporal Identity ◽  
And Function ◽  
Circuit Formation

The mechanisms specifying neuronal diversity are well-characterized, yet it remains unclear how or if these mechanisms regulate neural circuit assembly. To address this, we mapped the developmental origin of 160 interneurons from seven bilateral neural progenitors (neuroblasts), and identify them in a synapse-scale TEM reconstruction of the Drosophila larval CNS. We find that lineages concurrently build the sensory and motor neuropils by generating sensory and motor hemilineages in a Notch-dependent manner. Neurons in a hemilineage share common synaptic targeting within the neuropil, which is further refined based on neuronal temporal identity. Connectome analysis shows that hemilineage-temporal cohorts share common connectivity. Finally, we show that proximity alone cannot explain the observed connectivity structure, suggesting hemilineage/temporal identity confers an added layer of specificity. Thus, we demonstrate that the mechanisms specifying neuronal diversity also govern circuit formation and function, and that these principles are broadly applicable throughout the nervous system.

scholarly journals Müllerian inhibiting substance contributes to sex-linked biases in the brain and behavior

2009 ◽  
Vol 106 (17) ◽  
pp. 7203-7208 ◽  
Author(s):  
Pei-Yu Wang ◽  
Anna Protheroe ◽  
Andrew N. Clarkson ◽  
Floriane Imhoff ◽  
Kyoko Koishi ◽  
...  
Keyword(s):  
Motor Neurons ◽  
Reproductive Tract ◽  
Behavioral Traits ◽  
Spinal Motor Neurons ◽  
Müllerian Inhibiting Substance ◽  
Males And Females ◽  
Brain And Behavior ◽  
And Behavior ◽  
The Brain ◽  
Mullerian Inhibiting Substance

Many behavioral traits and most brain disorders are common to males and females but are more evident in one sex than the other. The control of these subtle sex-linked biases is largely unstudied and has been presumed to mirror that of the highly dimorphic reproductive nuclei. Sexual dimorphism in the reproductive tract is a product of Müllerian inhibiting substance (MIS), as well as the sex steroids. Males with a genetic deficiency in MIS signaling are sexually males, leading to the presumption that MIS is not a neural regulator. We challenge this presumption by reporting that most immature neurons in mice express the MIS-specific receptor (MISRII) and that male Mis−/− and Misrii−/− mice exhibit subtle feminization of their spinal motor neurons and of their exploratory behavior. Consequently, MIS may be a broad regulator of the subtle sex-linked biases in the nervous system.

scholarly journals Behavioral and Neuroanatomical Consequences of Cell-Type Specific Loss of Dopamine D2 Receptors in the Mouse Cerebral Cortex

2022 ◽  
Vol 15 ◽  
Author(s):  
Gloria S. Lee ◽  
Devon L. Graham ◽  
Brenda L. Noble ◽  
Taylor S. Trammell ◽  
Deirdre M. McCarthy ◽  
...  
Keyword(s):  
Cerebral Cortex ◽  
Motor Coordination ◽  
Cellular Level ◽  
D2 Receptors ◽  
Dopamine D2 Receptors ◽  
Inhibitory Neurons ◽  
Specific Loss ◽  
Dopamine D2 ◽  
And Behavior ◽  
Circuit Formation

Developmental dysregulation of dopamine D2 receptors (D2Rs) alters neuronal migration, differentiation, and behavior and contributes to the psychopathology of neurological and psychiatric disorders. The current study is aimed at identifying how cell-specific loss of D2Rs in the cerebral cortex may impact neurobehavioral and cellular development, in order to better understand the roles of this receptor in cortical circuit formation and brain disorders. We deleted D2R from developing cortical GABAergic interneurons (Nkx2.1-Cre) or from developing telencephalic glutamatergic neurons (Emx1-Cre). Conditional knockouts (cKO) from both lines, Drd2fl/fl, Nkx2.1-Cre+ (referred to as GABA-D2R-cKO mice) or Drd2fl/fl, Emx1-Cre+ (referred to as Glu-D2R-cKO mice), exhibited no differences in simple tests of anxiety-related or depression-related behaviors, or spatial or nonspatial working memory. Both GABA-D2R-cKO and Glu-D2R-cKO mice also had normal basal locomotor activity, but GABA-D2R-cKO mice expressed blunted locomotor responses to the psychotomimetic drug MK-801. GABA-D2R-cKO mice exhibited improved motor coordination on a rotarod whereas Glu-D2R-cKO mice were normal. GABA-D2R-cKO mice also exhibited spatial learning deficits without changes in reversal learning on a Barnes maze. At the cellular level, we observed an increase in PV+ cells in the frontal cortex of GABA-D2R-cKO mice and no noticeable changes in Glu-D2R-cKO mice. These data point toward unique and distinct roles for D2Rs within excitatory and inhibitory neurons in the regulation of behavior and interneuron development, and suggest that location-biased D2R pharmacology may be clinically advantageous to achieve higher efficacy and help avoid unwanted effects.

scholarly journals Temporal identity establishes columnar neuron morphology, connectivity, and function in a Drosophila navigation circuit

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
Luis F Sullivan ◽  
Timothy L Warren ◽  
Chris Q Doe
Keyword(s):  
Transcription Factor ◽  
Central Complex ◽  
Neuronal Diversity ◽  
Neuron Morphology ◽  
Neuron Number ◽  
Developmental Origin ◽  
Celestial Navigation ◽  
Transient Loss ◽  
Control Adult ◽  
And Function

The insect central complex (CX) is a conserved brain region containing 60 + neuronal subtypes, several of which contribute to navigation. It is not known how CX neuronal diversity is generated or how developmental origin of subtypes relates to function. We mapped the developmental origin of four key CX subtypes and found that neurons with similar origin have similar axon/dendrite targeting. Moreover, we found that the temporal transcription factor (TTF) Eyeless/Pax6 regulates the development of two recurrently-connected CX subtypes: Eyeless loss simultaneously produces ectopic P-EN neurons with normal axon/dendrite projections, and reduces the number of E-PG neurons. Furthermore, transient loss of Eyeless during development impairs adult flies’ capacity to perform celestial navigation. We conclude that neurons with similar developmental origin have similar connectivity, that Eyeless maintains equal E-PG and P-EN neuron number, and that Eyeless is required for the development of circuits that control adult navigation.

scholarly journals WNT signaling suppresses oligodendrogenesis via Ngn2-dependent direct inhibition of Olig2 expression

2020 ◽  
Vol 13 (1) ◽  
Author(s):  
Min Jiang ◽  
Dan Yu ◽  
Binghua Xie ◽  
Hao Huang ◽  
Wenwen Lu ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Motor Neurons ◽  
Promoter Activity ◽  
Neural Progenitor Cells ◽  
Luciferase Reporter ◽  
Oligodendrocyte Precursor Cells ◽  
Reporter Assay ◽  
Direct Inhibition ◽  
In Ovo ◽  
Oligodendrocyte Precursor

AbstractOlig2 transcription factor is essential for the maintenance of neural progenitor cells (NPCs) in the pMN domain and their sequential specification into motor neurons (MNs) and oligodendrocyte precursor cells (OPCs). The expression of Olig2 rapidly declines in newly generated MNs. However, Olig2 expression persists in later-born OPCs and antagonizes the expression of MN-related genes. The mechanism underlying the differential expression of Olig2 in MNs and oligodendrocytes remains unknown. Here, we report that activation of WNT/β-catenin signaling in pMN lineage cells abolished Olig2 expression coupled with a dramatic increase of Ngn2 expression. Luciferase reporter assay showed that Ngn2 inhibited Olig2 promoter activity. Overexpression of Ngn2-EnR transcription repressor blocked the expression of Olig2 in ovo. Our results suggest that down-regulation of WNT-Ngn2 signaling contributes to oligodendrogenesis from the pMN domain and the persistent Olig2 expression in OPCs.

scholarly journals Essential Functions of the Transcription Factor Npas4 in Neural Circuit Development, Plasticity, and Diseases

2020 ◽  
Vol 14 ◽  
Author(s):  
Jian Fu ◽  
Ouyang Guo ◽  
Zhihang Zhen ◽  
Junli Zhen
Keyword(s):  
Transcription Factor ◽  
Neural Circuit ◽  
Second Messenger ◽  
Synaptic Activity ◽  
Postsynaptic Potentials ◽  
Calcium Dependent ◽  
Neural Information ◽  
Formation Function ◽  
Second Messenger Pathways ◽  
Circuit Formation

Signaling from the synapse to nucleus is mediated by the integration and propagation of both membrane potential changes (postsynaptic potentials) and intracellular second messenger cascades. The electrical propagation of postsynaptic potentials allows for rapid neural information processing, while propagating second messenger pathways link synaptic activity to the transcription of genes required for neuronal survival and adaptive changes (plasticity) underlying circuit formation and learning. The propagation of activity-induced calcium signals to the cell nucleus is a major synapse-to-nucleus communication pathway. Neuronal PAS domain protein 4 (Npas4) is a recently discovered calcium-dependent transcription factor that regulates the activation of genes involved in the homeostatic regulation of excitatory–inhibitory balance, which is critical for neural circuit formation, function, and ongoing plasticity, as well as for defense against diseases such as epilepsy. Here, we summarize recent findings on the neuroprotective functions of Npas4 and the potential of Npas4 as a therapeutic target for the treatment of acute and chronic diseases of the central nervous system.

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