Catenin signaling controls phrenic motor neuron development and function during a narrow temporal window

Phrenic Motor Column (PMC) neurons are a specialized subset of motor neurons (MNs) that provide the only motor innervation to the diaphragm muscle and are therefore essential for survival. Despite their critical role, the mechanisms that control phrenic MN development and function are not well understood. Here, we show that catenin-mediated cadherin adhesive function is required for multiple aspects of phrenic MN development. Deletion of β- and γ-catenin from MN progenitors results in perinatal lethality and a severe reduction in phrenic MN bursting activity. In the absence of catenin signaling, phrenic MN topography is eroded, MN clustering is lost and phrenic axons and dendrites fail to grow appropriately. Despite the essential requirement for catenins in early phrenic MN development, they appear to be dispensable for phrenic MN maintenance, as catenin deletion from postmitotic MNs does not impact phrenic MN topography or function. Our data reveal a fundamental role for catenins in PMC development and suggest that distinct mechanisms are likely to control PMC maintenance.

[1]  Allyson J. Merrell,et al.  Fibroblast-derived Hgf controls recruitment and expansion of muscle during morphogenesis of the mammalian diaphragm , 2022, eLife.

[2]  L. Landmesser,et al.  Coordinated cadherin functions sculpt respiratory motor circuit connectivity , 2022, bioRxiv.

[3]  I. Martinez-Garay Molecular Mechanisms of Cadherin Function During Cortical Migration , 2020, Frontiers in Cell and Developmental Biology.

[4]  L. Landmesser,et al.  Phrenic-specific transcriptional programs shape respiratory motor output , 2020, eLife.

[5]  L. Abbott,et al.  Positional Strategies for Connection Specificity and Synaptic Organization in Spinal Sensory-Motor Circuits , 2019, Neuron.

[6]  Xin Duan,et al.  Organization of motor pools depends on the combined function of N-cadherin and type II cadherins , 2019, Development.

[7]  G. Fortin,et al.  Teashirt 1 (Tshz1) is essential for the development, survival and function of hypoglossal and phrenic motor neurons in mouse , 2019, Development.

[8]  J. Sanes,et al.  Cadherin Combinations Recruit Dendrites of Distinct Retinal Neurons to a Shared Interneuronal Scaffold , 2018, Neuron.

[9]  T. Jessell,et al.  Nuclear Organization in the Spinal Cord Depends on Motor Neuron Lamination Orchestrated by Catenin and Afadin Function. , 2018, Cell reports.

[10]  J. Sanes,et al.  Heterophilic Type II Cadherins Are Required for High-Magnitude Synaptic Potentiation in the Hippocampus , 2017, Neuron.

[11]  Donna M. Martin,et al.  Genetic specification of left–right asymmetry in the diaphragm muscles and their motor innervation , 2017, eLife.

[12]  J. Arikkath,et al.  Cadherins and catenins in dendrite and synapse morphogenesis , 2015, Cell adhesion & migration.

[13]  Raunak Basu,et al.  The classic cadherins in synaptic specificity , 2015, Cell adhesion & migration.

[14]  J. Sanes,et al.  Type II Cadherins Guide Assembly of a Direction-Selective Retinal Circuit , 2014, Cell.

[15]  M. Kyba,et al.  Reconstruction of phrenic neuron identity in embryonic stem cell-derived motor neurons , 2014, Development.

[16]  T. Iwatsubo,et al.  CLAC-P/Collagen Type XXV Is Required for the Intramuscular Innervation of Motoneurons during Neuromuscular Development , 2014, The Journal of Neuroscience.

[17]  J. Dasen,et al.  Sustained Hox5 Gene Activity is Required for Respiratory Motor Neuron Development , 2012, Nature Neuroscience.

[18]  John J. Greer,et al.  Control of breathing activity in the fetus and newborn. , 2012, Comprehensive Physiology.

[19]  M. Takeichi,et al.  Cadherins in brain morphogenesis and wiring. , 2012, Physiological reviews.

[20]  T. Jessell,et al.  Motor Neuron Position and Topographic Order Imposed by β- and γ-Catenin Activities , 2011, Cell.

[21]  Mark Ellisman,et al.  Cadherin-9 Regulates Synapse-Specific Differentiation in the Developing Hippocampus , 2011, Neuron.

[22]  Phong L. Nguyen,et al.  Cadherin-6 Mediates Axon-Target Matching in a Non-Image-Forming Visual Circuit , 2011, Neuron.

[23]  N. Golenhofen,et al.  Different Regulation of N-Cadherin and Cadherin-11 in Rat Hippocampus , 2010, Cell communication & adhesion.

[24]  D. Benson,et al.  Cadherin‐8 and N‐cadherin differentially regulate pre‐ and postsynaptic development of the hippocampal mossy fiber pathway , 2008, Hippocampus.

[25]  T. Gao,et al.  Retrograde regulation of motoneuron differentiation by muscle β-catenin , 2008, Nature Neuroscience.

[26]  James Briscoe,et al.  Interpretation of the sonic hedgehog morphogen gradient by a temporal adaptation mechanism , 2007, Nature.

[27]  M. Takeichi,et al.  Cadherin-8 Is Required for the First Relay Synapses to Receive Functional Inputs from Primary Sensory Afferents for Cold Sensation , 2007, The Journal of Neuroscience.

[28]  Silvia Arber,et al.  Target-Induced Transcriptional Control of Dendritic Patterning and Connectivity in Motor Neurons by the ETS Gene Pea3 , 2006, Cell.

[29]  K. Kawakami,et al.  Cadherin is required for dendritic morphogenesis and synaptic terminal organization of retinal horizontal cells , 2006, Development.

[30]  J. Greer,et al.  Perinatal development of respiratory motoneurons , 2005, Respiratory Physiology & Neurobiology.

[31]  Liqun Luo,et al.  Diverse Functions of N-Cadherin in Dendritic and Axonal Terminal Arborization of Olfactory Projection Neurons , 2004, Neuron.

[32]  R. Malenka,et al.  β-catenin is critical for dendritic morphogenesis , 2003, Nature Neuroscience.

[33]  Stephen W. Wilson,et al.  N-cadherin mediates retinal lamination, maintenance of forebrain compartments and patterning of retinal neurites , 2003, Development.

[34]  T. Jessell,et al.  Regulation of Motor Neuron Pool Sorting by Differential Expression of Type II Cadherins , 2002, Cell.

[35]  A. McMahon,et al.  Inactivation of the beta-catenin gene by Wnt1-Cre-mediated deletion results in dramatic brain malformation and failure of craniofacial development. , 2001, Development.

[36]  O. Bozdagi,et al.  Increasing Numbers of Synaptic Puncta during Late-Phase LTP N-Cadherin Is Synthesized, Recruited to Synaptic Sites, and Required for Potentiation , 2000, Neuron.

[37]  T. Manabe,et al.  Loss of Cadherin-11 Adhesion Receptor Enhances Plastic Changes in Hippocampal Synapses and Modifies Behavioral Responses , 2000, Molecular and Cellular Neuroscience.

[38]  G. Banker,et al.  Differential effects of NgCAM and N-cadherin on the development of axons and dendrites by cultured hippocampal neurons , 2000, Journal of neurocytology.

[39]  Hidekazu Tanaka,et al.  N-Cadherin Redistribution during Synaptogenesis in Hippocampal Neurons , 1998, The Journal of Neuroscience.

[40]  Takayoshi Inoue,et al.  Neuronal Circuits Are Subdivided by Differential Expression of Type-II Classic Cadherins in Postnatal Mouse Brains , 1997, Molecular and Cellular Neuroscience.

[41]  M. Takeichi,et al.  The catenin/cadherin adhesion system is localized in synaptic junctions bordering transmitter release zones , 1996, The Journal of cell biology.

[42]  C. Holt,et al.  Cadherin Function Is Required for Axon Outgrowth in Retinal Ganglion Cells In Vivo , 1996, Neuron.

[43]  D. Colman,et al.  A Model for Central Synaptic Junctional Complex Formation Based on the Differential Adhesive Specificities of the Cadherins , 1996, Neuron.

[44]  M. Yamagata,et al.  Lamina-specific expression of adhesion molecules in developing chick optic tectum , 1995, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[45]  T. Jessell,et al.  Topographic organization of embryonic motor neurons defined by expression of LIM homeobox genes , 1994, Cell.

[46]  B. Lowell,et al.  Development and phenotype of ChAT-IRES-Cre mice MGI Direct Data Submission , 2006 .