scholarly journals Temporal patterning of apical progenitors and their daughter neurons in the developing neocortex

Science ◽  
2019 ◽  
Vol 364 (6440) ◽  
pp. eaav2522 ◽  
Author(s):  
L. Telley ◽  
G. Agirman ◽  
J. Prados ◽  
N. Amberg ◽  
S. Fièvre ◽  
...  
Keyword(s):  
Ventricular Zone ◽  
Mouse Embryos ◽  
High Temporal Resolution ◽  
Neuronal Diversity ◽  
Core Set ◽  
Evolutionarily Conserved ◽  
Repressor Complex ◽  
Age Dependent ◽  
Developing Neocortex ◽  
Successive Generations

During corticogenesis, distinct subtypes of neurons are sequentially born from ventricular zone progenitors. How these cells are molecularly temporally patterned is poorly understood. We used single-cell RNA sequencing at high temporal resolution to trace the lineage of the molecular identities of successive generations of apical progenitors (APs) and their daughter neurons in mouse embryos. We identified a core set of evolutionarily conserved, temporally patterned genes that drive APs from internally driven to more exteroceptive states. We found that the Polycomb repressor complex 2 (PRC2) epigenetically regulates AP temporal progression. Embryonic age–dependent AP molecular states are transmitted to their progeny as successive ground states, onto which essentially conserved early postmitotic differentiation programs are applied, and are complemented by later-occurring environment-dependent signals. Thus, epigenetically regulated temporal molecular birthmarks present in progenitors act in their postmitotic progeny to seed adult neuronal diversity.

scholarly journals Simultaneous production of diverse neuronal subtypes during early corticogenesis

2018 ◽  
Author(s):  
E. Magrinelli ◽  
R. J. Wagener ◽  
D. Jabaudon
Keyword(s):  
Deep Layer ◽  
Ventricular Zone ◽  
Neuronal Cell ◽  
Cell Types ◽  
Superficial Layer ◽  
High Temporal Resolution ◽  
Fine Grained ◽  
Molecular Identity ◽  
Deep Layers ◽  
Successive Generations

AbstractThe circuits of the neocortex are composed of a broad diversity of neuronal cell types, which can be distinguished by their laminar location, molecular identity, and connectivity. During embryogenesis, successive generations of glutamatergic neurons are sequentially born from progenitors located in germinal zones below the cortex. In this process, the earliest-born generations of neurons differentiate to reside in deep layers, while later-born daughter neurons reside in more superficial layers. Although the aggregate competence of progenitors to produce successive subtypes of neurons progresses as corticogenesis proceeds, a fine-grained temporal understanding of how neuronal subtypes are sequentially produced is still missing. Here, we use FlashTag, a high temporal resolution labeling approach, to follow the fate of the simultaneously-born daughter neurons of ventricular zone progenitors at multiple stages of corticogenesis. Our findings reveal a bimodal regulation in the diversity of neurons being produced at single time points of corticogenesis. Initially, distinct subtypes of deep-layer neurons are simultaneously produced, as defined by their laminar location, molecular identity and connectivity. Later on, instead, instantaneous neuronal production is homogeneous and the distinct superficial-layer neurons subtypes are sequentially produced. These findings suggest that early-born, deep-layer neurons have a less determined fate potential than later-born superficial layer neurons, which may reflect the progressive implementation of pre-and/or post-mitotic mechanisms controlling neuronal fate reliability.

scholarly journals Coupling progenitor and neuronal diversity in the developing neocortex

FEBS Letters ◽  
2017 ◽  
Vol 591 (24) ◽  
pp. 3960-3977 ◽  
Author(s):  
Subashika Govindan ◽  
Denis Jabaudon
Keyword(s):  
Neuronal Diversity ◽  
Developing Neocortex

scholarly journals Evolutionarily conserved regulation of embryonic fast-twitch skeletal muscle differentiation by Pbx factors

2020 ◽  
Author(s):  
Gist H. Farr ◽  
Bingsi Li ◽  
Maurizio Risolino ◽  
Nathan M. Johnson ◽  
Zizhen Yao ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Muscle Development ◽  
Muscle Differentiation ◽  
Mouse Embryos ◽  
Fast Muscle ◽  
Fiber Types ◽  
Skeletal Muscle Differentiation ◽  
Homeodomain Proteins ◽  
Evolutionarily Conserved ◽  
Fast Twitch

SummaryVertebrate skeletal muscles are composed of both slow-twitch and fast-twitch fiber types. How the differentiation of distinct fiber types is activated during embryogenesis is not well characterized. Skeletal muscle differentiation is initiated by the activity of the myogenic basic helix-loop-helix (bHLH) transcription factors Myf5, Myod1, Myf6, and Myog. Myod1 functions as a muscle master regulatory factor and directly activates muscle differentiation genes, including those specific to both slow and fast muscle fibers. Our previous studies showed that Pbx TALE-class homeodomain proteins bind with Myod1 on the promoter of the zebrafish fast muscle gene mylpfa and are required for proper activation of mylpfa expression and the fast-twitch muscle-specific differentiation program in zebrafish embryos. Pbx proteins have also been shown to bind regulatory regions of muscle differentiation genes in mammalian muscle cells in culture. Here, we use new zebrafish mutant strains to confirm the essential roles of zebrafish Pbx factors in embryonic fast muscle differentiation. Furthermore, we examine the requirements for Pbx genes in mouse embryonic skeletal muscle differentiation, an area that has not been investigated in the mammalian embryo. Removing Pbx1 function from skeletal muscle in Myf5Cre/+;Pbx1fl/fl mouse embryos has minor effects on embryonic muscle development. However, concomitantly deleting Pbx2 function in Myf5Cre/+;Pbx1fl/fl;Pbx2-/- mouse embryos causes delayed activation and reduced expression of fast muscle differentiation genes. In the mouse, Pbx1/Pbx2-dependent fast muscle genes closely match those that have been previously shown to be dependent on murine Six1 and Six4. This work establishes evolutionarily conserved requirements for Pbx factors in embryonic fast muscle differentiation. Our studies are revealing how Pbx homeodomain proteins help direct specific cellular differentiation pathways.

scholarly journals The role of ZFP57 and additional KRAB-zinc finger proteins in the maintenance of human imprinted methylation and multi-locus imprinting disturbances

2020 ◽  
Vol 48 (20) ◽  
pp. 11394-11407
Author(s):  
Ana Monteagudo-Sánchez ◽  
Jose Ramon Hernandez Mora ◽  
Carlos Simon ◽  
Adam Burton ◽  
Jair Tenorio ◽  
...  
Keyword(s):  
Zinc Finger ◽  
Expression Profiling ◽  
Zinc Finger Proteins ◽  
Early Embryogenesis ◽  
Mouse Embryos ◽  
Parental Origin ◽  
Embryonic Genome ◽  
Repressor Complex ◽  
Genome Activation

Abstract Genomic imprinting is an epigenetic process regulated by germline-derived DNA methylation that is resistant to embryonic reprogramming, resulting in parental origin-specific monoallelic gene expression. A subset of individuals affected by imprinting disorders (IDs) displays multi-locus imprinting disturbances (MLID), which may result from aberrant establishment of imprinted differentially methylated regions (DMRs) in gametes or their maintenance in early embryogenesis. Here we investigated the extent of MLID in a family harbouring a ZFP57 truncating variant and characterize the interactions between human ZFP57 and the KAP1 co-repressor complex. By ectopically targeting ZFP57 to reprogrammed loci in mouse embryos using a dCas9 approach, we confirm that ZFP57 recruitment is sufficient to protect oocyte-derived methylation from reprogramming. Expression profiling in human pre-implantation embryos and oocytes reveals that unlike in mice, ZFP57 is only expressed following embryonic-genome activation, implying that other KRAB-zinc finger proteins (KZNFs) recruit KAP1 prior to blastocyst formation. Furthermore, we uncover ZNF202 and ZNF445 as additional KZNFs likely to recruit KAP1 to imprinted loci during reprogramming in the absence of ZFP57. Together, these data confirm the perplexing link between KZFPs and imprint maintenance and highlight the differences between mouse and humans in this respect.

scholarly journals Crumbs regulates rhodopsin transport by interacting with and stabilizing myosin V

2011 ◽  
Vol 195 (5) ◽  
pp. 827-838 ◽  
Author(s):  
Shirin Meher Pocha ◽  
Anna Shevchenko ◽  
Elisabeth Knust
Keyword(s):  
Retinal Degeneration ◽  
Molecular Mechanism ◽  
Photoreceptor Cell ◽  
Myosin V ◽  
Light Sensing ◽  
Evolutionarily Conserved ◽  
Severe Reduction ◽  
Deficient Medium ◽  
Age Dependent ◽  
First Time

The evolutionarily conserved Crumbs (Crb) complex is crucial for photoreceptor morphogenesis and homeostasis. Loss of Crb results in light-dependent retinal degeneration, which is prevented by feeding mutant flies carotenoid-deficient medium. This suggests a defect in rhodopsin 1 (Rh1) processing, transport, and/or signaling, causing degeneration; however, the molecular mechanism of this remained elusive. In this paper, we show that myosin V (MyoV) coimmunoprecipitated with the Crb complex and that loss of crb led to severe reduction in MyoV levels, which could be rescued by proteasomal inhibition. Loss of MyoV in crb mutant photoreceptors was accompanied by defective transport of the MyoV cargo Rh1 to the light-sensing organelle, the rhabdomere. This resulted in an age-dependent accumulation of Rh1 in the photoreceptor cell (PRC) body, a well-documented trigger of degeneration. We conclude that Crb protects against degeneration by interacting with and stabilizing MyoV, thereby ensuring correct Rh1 trafficking. Our data provide, for the first time, a molecular mechanism for the light-dependent degeneration of PRCs observed in crb mutant retinas.

scholarly journals A Protein-trap allele reveals roles for Drosophila ATF4 in photoreceptor degeneration, oogenesis and wing development

2021 ◽  
Author(s):  
Deepika Vasudevan ◽  
Hidetaka Katow ◽  
Huai-Wei Huang ◽  
Grace Tang ◽  
Hyung Don Ryoo
Keyword(s):  
Control Mechanisms ◽  
Loss Of Function ◽  
Pupal Development ◽  
Gfp Fusion Protein ◽  
Drosophila Model ◽  
Evolutionarily Conserved ◽  
Age Dependent ◽  
Cellular Stressors ◽  
Trap Line

Metazoans have evolved various quality control mechanisms to cope with cellular stress inflicted by external and physiological conditions. ATF4 is a major effector of the Integrated Stress Response (ISR), an evolutionarily conserved pathway that mediates adaptation to various cellular stressors. Loss of function of Drosophila ATF4, encoded by the gene cryptocephal (crc), results in lethality during pupal development. The roles of crc in Drosophila disease models and in adult tissue homeostasis thus remain poorly understood. Here, we report that a protein-trap MiMIC insertion in the crc locus generates a crc-GFP fusion protein that allows visualization of crc activity in vivo. This allele also acts as a hypomorphic mutant that uncovers previously unknown roles for crc. Specifically, the crc protein-trap line shows crc-GFP induction in a Drosophila model for Retinitis Pigmentosa (RP). This crc allele renders flies more vulnerable to amino acid deprivation and age-dependent retinal degeneration. These mutants also show defects in wing veins and oocyte maturation. Together, our data reveal previously unknown roles for crc in development, cellular homeostasis and photoreceptor survival.

scholarly journals Impaired peroxisomal import in Drosophila hepatocyte-like cells induces cardiac dysfunction through the pro-inflammatory cytokine Upd3

2019 ◽  
Author(s):  
Kerui Huang ◽  
Ting Miao ◽  
Kai Chang ◽  
Ping Kang ◽  
Qiuhan Jiang ◽  
...  
Keyword(s):  
Cardiac Dysfunction ◽  
Inflammatory Cytokine ◽  
Cytokine Signaling ◽  
Over Expression ◽  
Autonomous Regulation ◽  
Age Related ◽  
Evolutionarily Conserved ◽  
Age Dependent ◽  
Import Receptor

AbstractAge is a major risk factor for cardiovascular diseases. Currently, the non-autonomous regulation of age-related cardiac dysfunction is poorly understood. In the present study, we discover that age-dependent induction of cytokine unpaired 3 (Upd3) in Drosophila oenocytes (hepatocyte-like cells), due to a dampened peroxisomal import function, is the primary non-autonomous mechanism for elevated arrhythmicity in old hearts. We show that Upd3 is significantly up-regulated (52-fold) in aged oenocytes. Oenocyte-specific knockdown of Upd3 is sufficient to block aging-induced cardiac arrhythmia. We further show that the age-dependent induction of Upd3 is triggered by impaired peroxisomal import and elevated JNK signaling in aged oenocytes. Intriguingly, oenocyte-specific over-expression of Pex5, the key peroxisomal import receptor, restores peroxisomal import, blocks age-related Upd3 induction, and alleviates aging- and paraquat-induced cardiac arrhythmicity. Thus, our studies identify an important role of the evolutionarily conserved pro-inflammatory cytokine signaling and hepatocyte-specific peroxisomal import in mediating non-autonomous regulation of cardiac aging.

scholarly journals Translational control of polyamine metabolism by CNBP is required for Drosophila locomotor function

2021 ◽  
Author(s):  
Sonia Coni ◽  
Federica A. Falconio ◽  
Marta Marzullo ◽  
Marzia Munafò ◽  
Benedetta Zuliani ◽  
...  
Keyword(s):  
Translational Control ◽  
Muscle Function ◽  
Rna Binding ◽  
Polyamine Metabolism ◽  
List Type ◽  
Mammalian Development ◽  
Locomotor Function ◽  
Evolutionarily Conserved ◽  
Age Dependent ◽  
Toxic Rna

ABSTRACTMicrosatellite expansions of CCTG repeats in the CNBP gene leads to accumulation of toxic RNA and have been associated to DM2. However, it is still unclear whether the dystrophic phenotype is also linked to CNBP decrease, a conserved CCHC-type zinc finger RNA binding protein that regulates translation and is required for mammalian development.Here we show that depletion of Drosophila CNBP in muscles causes age-dependent locomotor defects that are correlated with impaired polyamine metabolism. We demonstrate that the levels of ornithine decarboxylase (ODC) and polyamines are significantly reduced upon dCNBP depletion. Of note, we show a reduction of the CNBP-polyamine axis in muscle from DM2 patients. Mechanistically, we provide evidence that dCNBP controls polyamine metabolism through binding dOdc mRNA and regulating its translation. Remarkably, the locomotor defect of dCNBP-deficient flies is rescued by either polyamine supplementation or dOdc1 overexpression. We suggest that this dCNBP function is evolutionarily conserved in vertebrates with relevant implications for CNBP-related pathophysiological conditions.GRAPHICAL ABSTRACTCNBP controls muscle function by regulating the polyamine metabolismLack of dCNBP impairs locomotor function through ODC-polyamine downregulationdCNBP binds dOdc mRNA and regulates its translationPolyamine supplementation or dOdc1 reconstitution rescues locomotor defectsCNBP-ODC-polyamine levels are reduced in muscle of DM2 patients

scholarly journals Targeted Ablation and Reorganization of the Principal Preplate Neurons and Their Neuroblasts Identified by Golli Promoter Transgene Expression in the Neocortex of Mice

ASN NEURO ◽  
2009 ◽  
Vol 1 (4) ◽  
pp. AN20090038 ◽  
Author(s):  
Yuan-Yun Xie ◽  
Erin Jacobs ◽  
Robin Fisher
Keyword(s):  
Fluorescent Protein ◽  
Ventricular Zone ◽  
Vertical Gradient ◽  
Prenatal Development ◽  
Specific Cell ◽  
Genetic Ablation ◽  
Developing Neocortex ◽  
Total Complement ◽  
Green Fluorescent ◽  
Simplex Virus

The present study delineates the cellular responses of dorsal pallium to targeted genetic ablation of the principal preplate neurons of the neocortex. Ganciclovir treatment during prenatal development (E11-E13; where E is embryonic day) of mice selectively killed cells with shared S-phase vulnerability and targeted expression of a GPT [golli promoter transgene, linked to HSV-TK (herpes simplex virus-thymidine kinase), τ-eGFP (τ-enhanced green fluorescent protein) and lacZ (lacZ galactosidase) reporters] localized in preplate neurons. Morphogenetic fates of attacked neurons and neuroblasts, and their successors, were assessed by multiple labelling in time-series comparisons between ablated (HSV-TK+/0) and control (HSV-TK0/0) littermates. During ablation generation, neocortical growth was suppressed, and compensatory reorganization of non-GPT ventricular zone progenitors of dorsal pallium produced replacements for killed GPT neuroblasts. Replacement and surviving GPT neuroblasts then produced replacements for killed GPT neurons. Near-normal restoration of their complement delayed the settlement of GPT neurons into the reconstituted preplate, which curtailed the outgrowth of pioneer corticofugal axons. Based on this evidence, we conclude that specific cell killing in ablated mice can eliminate a major fraction of GPT neurons, with insignificant bystander killing. Also, replacement GPT neurons in ablated mice originate exclusively by proliferation from intermediate progenitor GPT neuroblasts, whose complement is maintained by non-GPT progenitors for inductive regulation of the total complement of GPT neurons. Finally, GPT neurons in both normal and ablated mice meet all morphogenetic criteria, including the ‘outside-in’ vertical gradient of settlement, presently used to identify principal preplate neurons. In ablated mice, delayed organization of these neurons desynchronizes and isolates developing neocortex from the rest of the brain, and permanently impairs its connectivity.

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