scholarly journals CRISPR/Cas9 interrogation of the mouse Pcdhg gene cluster reveals a crucial isoform-specific role for Pcdhgc4

2019 ◽  
Author(s):  
Andrew M. Garrett ◽  
Peter J. Bosch ◽  
David M. Steffen ◽  
Leah C. Fuller ◽  
Charles G. Marcucci ◽  
...  
Keyword(s):  
Gene Cluster ◽  
Molecular Mechanisms ◽  
Neural Circuit ◽  
Neuronal Survival ◽  
Allelic Series ◽  
Isoform Diversity ◽  
Variable Exon ◽  
Human Orthologue ◽  
Mutant Lines ◽  
Circuit Formation

ABSTRACTThe mammalian Pcdhg gene cluster encodes a family of 22 cell adhesion molecules, the gamma-Protocadherins (γ-Pcdhs), critical for neuronal survival and neural circuit formation. The extent to which isoform diversity–aγ-Pcdh hallmark–is required for their functions remains unclear. We used a CRISPR/Cas9 approach to reduce isoform diversity, targeting each Pcdhg variable exon with pooled sgRNAs to generate an allelic series of 26 mouse lines with 1 to 21 isoforms disrupted via discrete indels at guide sites and/or larger deletions/rearrangements. Analysis of 5 mutant lines indicates that postnatal viability and neuronal survival do not require isoform diversity. Surprisingly, as it is the only γ-Pcdh that cannot independently engage in homophilic trans-interactions, we find that γC4, encoded by Pcdhgc4, is the only critical isoform. Because the human orthologue is the only PCDHG gene constrained in humans, our results indicate a conserved γC4 function that likely involves distinct molecular mechanisms.

scholarly journals Strip1 regulates retinal ganglion cell survival by suppressing Jun-mediated apoptosis to promote retinal neural circuit formation

2021 ◽  
Author(s):  
Mai Ahmed ◽  
Yutaka Kojima ◽  
Ichiro Masai
Keyword(s):  
Molecular Mechanisms ◽  
Neural Circuit ◽  
Ganglion Cells ◽  
Plexiform Layer ◽  
Bipolar Cells ◽  
Inner Plexiform Layer ◽  
Retinal Ganglion ◽  
Interacting Protein ◽  
Retina Development ◽  
Circuit Formation

In the vertebrate retina, an interplay between retinal ganglion cells (RGCs), amacrine and bipolar cells establishes a synaptic layer called the inner plexiform layer (IPL). This circuit conveys signals from photoreceptors to visual centers in the brain. However, the molecular mechanisms involved in its development remain poorly understood. Striatin-interacting protein 1 (Strip1) is a core component of the STRIPAK complex, and it has shown emerging roles in embryonic morphogenesis. Here, we uncover the importance of Strip1 in inner retina development. Using zebrafish, we show that loss of Strip1 causes defects in IPL formation. In strip1 mutants, RGCs undergo dramatic cell death shortly after birth. Amacrine and bipolar cells subsequently invade the degenerating RGC layer, leading to a disorganized IPL. Thus, Strip1 promotes IPL formation through RGC maintenance. Mechanistically, zebrafish Strip1 interacts with its STRIPAK partner, Striatin3, to promote RGC survival by suppressing Jun-mediated apoptosis. In addition to its function in RGC maintenance, Strip1 is required for RGC dendritic patterning, which likely contributes to proper IPL formation. Taken together, we propose that a series of Strip1-mediated regulatory events coordinates inner retinal circuit formation by maintaining RGCs during development, which ensures proper positioning and neurite patterning of inner retinal neurons.

scholarly journals Molecular mechanisms underlying neural circuit formation

2009 ◽  
Vol 19 (2) ◽  
pp. 162-167 ◽  
Author(s):  
Bai Lu ◽  
Kuan Hong Wang ◽  
Akinao Nose
Keyword(s):  
Molecular Mechanisms ◽  
Neural Circuit ◽  
Circuit Formation

scholarly journals Axon guidance at the midline – a live imaging perspective

2020 ◽  
Author(s):  
Alexandre Dumoulin ◽  
Nikole R. Zuñiga ◽  
Esther T. Stoeckli
Keyword(s):  
Molecular Mechanisms ◽  
Neural Circuit ◽  
Surface Expression ◽  
Growth Cones ◽  
Live Imaging ◽  
Growth Speed ◽  
Intermediate Target ◽  
Commissural Axons ◽  
Circuit Formation

ABSTRACTDuring neural circuit formation, axons navigate several choice points to reach their final target. At each one of these intermediate targets, growth cones need to switch responsiveness from attraction to repulsion in order to move on. Molecular mechanisms that allow for the precise timing of surface expression of a new set of receptors that support the switch in responsiveness are difficult to study in vivo. Mostly, mechanisms are inferred from the observation of snapshots of many different growth cones analyzed in different preparations of tissue harvested at distinct time points. However, to really understand the behavior of growth cones at choice points, a single growth cone should be followed arriving at and leaving the intermediate target.Here, we describe a spinal cord preparation that allows for live imaging of individual axons during navigation in their intact environment. The possibility to observe single growth cones navigating their intermediate target allows for measuring growth speed, changes in morphology, or aberrant behavior. Moreover, observation of the intermediate target – the floor plate – revealed its active participation and interaction with commissural axons during midline crossing.Summary statementLive tracking of single growth cones is more informative about axonal behavior during navigation than inference of behavior from the analyses of snapshots of different growth cones.

scholarly journals Architects in neural circuit design: Glia control neuron numbers and connectivity

2013 ◽  
Vol 203 (3) ◽  
pp. 395-405 ◽  
Author(s):  
Megan M. Corty ◽  
Marc R. Freeman
Keyword(s):  
Nervous System ◽  
Circuit Design ◽  
Glial Cells ◽  
Neural Development ◽  
Molecular Mechanisms ◽  
Neural Circuit ◽  
Neuronal Circuit ◽  
Circuit Formation

Glia serve many important functions in the mature nervous system. In addition, these diverse cells have emerged as essential participants in nearly all aspects of neural development. Improved techniques to study neurons in the absence of glia, and to visualize and manipulate glia in vivo, have greatly expanded our knowledge of glial biology and neuron–glia interactions during development. Exciting studies in the last decade have begun to identify the cellular and molecular mechanisms by which glia exert control over neuronal circuit formation. Recent findings illustrate the importance of glial cells in shaping the nervous system by controlling the number and connectivity of neurons.

scholarly journals Trans-Axonal Signaling in Neural Circuit Wiring

2020 ◽  
Vol 21 (14) ◽  
pp. 5170 ◽  
Author(s):  
Olivia Spead ◽  
Fabienne E. Poulain
Keyword(s):  
Molecular Mechanisms ◽  
Neural Circuits ◽  
Neural Circuit ◽  
Target Selection ◽  
Synaptic Connectivity ◽  
Recent Advances ◽  
Complex Process ◽  
Circuit Formation

The development of neural circuits is a complex process that relies on the proper navigation of axons through their environment to their appropriate targets. While axon–environment and axon–target interactions have long been known as essential for circuit formation, communication between axons themselves has only more recently emerged as another crucial mechanism. Trans-axonal signaling governs many axonal behaviors, including fasciculation for proper guidance to targets, defasciculation for pathfinding at important choice points, repulsion along and within tracts for pre-target sorting and target selection, repulsion at the target for precise synaptic connectivity, and potentially selective degeneration for circuit refinement. This review outlines the recent advances in identifying the molecular mechanisms of trans-axonal signaling and discusses the role of axon–axon interactions during the different steps of neural circuit formation.

scholarly journals Molecular Mechanisms of Neural Circuit Development and Regeneration

2021 ◽  
Vol 22 (9) ◽  
pp. 4593
Author(s):  
Lieve Moons ◽  
Lies De Groef
Keyword(s):  
Human Brain ◽  
Molecular Mechanisms ◽  
Neural Circuit ◽  
Circuit Development

The human brain contains 86 billion neurons [...]

scholarly journals Implications of Extended Inhibitory Neuron Development

2021 ◽  
Vol 22 (10) ◽  
pp. 5113
Author(s):  
Jae-Yeon Kim ◽  
Mercedes F. Paredes
Keyword(s):  
Neural Circuit ◽  
Inhibitory Neuron ◽  
Postnatal Period ◽  
Specific Pattern ◽  
Inhibitory Neurons ◽  
Gabaergic Interneuron ◽  
Gabaergic Interneurons ◽  
Neuron Development ◽  
Cortical Regions ◽  
Circuit Formation

A prolonged developmental timeline for GABA (γ-aminobutyric acid)-expressing inhibitory neurons (GABAergic interneurons) is an amplified trait in larger, gyrencephalic animals. In several species, the generation, migration, and maturation of interneurons take place over several months, in some cases persisting after birth. The late integration of GABAergic interneurons occurs in a region-specific pattern, especially during the early postnatal period. These changes can contribute to the formation of functional connectivity and plasticity, especially in the cortical regions responsible for higher cognitive tasks. In this review, we discuss GABAergic interneuron development in the late gestational and postnatal forebrain. We propose the protracted development of interneurons at each stage (neurogenesis, neuronal migration, and network integration), as a mechanism for increased complexity and cognitive flexibility in larger, gyrencephalic brains. This developmental feature of interneurons also provides an avenue for environmental influences to shape neural circuit formation.

Optical survey of neural circuit formation in the embryonic chick vagal pathway

2004 ◽  
Vol 19 (5) ◽  
pp. 1217-1225 ◽  
Author(s):  
Katsushige Sato ◽  
Naohisa Miyakawa ◽  
Yoko Momose-Sato
Keyword(s):  
Neural Circuit ◽  
Embryonic Chick ◽  
Vagal Pathway ◽  
Circuit Formation

Role of microRNAs in Semaphorin function and neural circuit formation

2013 ◽  
Vol 24 (3) ◽  
pp. 146-155 ◽  
Author(s):  
Marie-Laure Baudet ◽  
Anaïs Bellon ◽  
Christine E. Holt
Keyword(s):  
Neural Circuit ◽  
Circuit Formation
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