scholarly journals TALPID3/KIAA0586 Regulates Multiple Aspects of Neuromuscular Patterning During Gastrointestinal Development in Animal Models and Human

2021 ◽  
Vol 14 ◽  
Author(s):  
Jean Marie Delalande ◽  
Nandor Nagy ◽  
Conor J. McCann ◽  
Dipa Natarajan ◽  
Julie E. Cooper ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Animal Models ◽  
Neural Crest ◽  
Protein Trafficking ◽  
Neural Crest Cells ◽  
Conditional Knockout ◽  
Gi Tract ◽  
Knockout Mouse Model ◽  
Conditional Knockout Mouse ◽  
Epithelial Development

TALPID3/KIAA0586 is an evolutionary conserved protein, which plays an essential role in protein trafficking. Its role during gastrointestinal (GI) and enteric nervous system (ENS) development has not been studied previously. Here, we analyzed chicken, mouse and human embryonic GI tissues with TALPID3 mutations. The GI tract of TALPID3 chicken embryos was shortened and malformed. Histologically, the gut smooth muscle was mispatterned and enteric neural crest cells were scattered throughout the gut wall. Analysis of the Hedgehog pathway and gut extracellular matrix provided causative reasons for these defects. Interestingly, chicken intra-species grafting experiments and a conditional knockout mouse model showed that ENS formation did not require TALPID3, but was dependent on correct environmental cues. Surprisingly, the lack of TALPID3 in enteric neural crest cells (ENCC) affected smooth muscle and epithelial development in a non-cell-autonomous manner. Analysis of human gut fetal tissues with a KIAA0586 mutation showed strikingly similar findings compared to the animal models demonstrating conservation of TALPID3 and its necessary role in human GI tract development and patterning.

scholarly journals Specificity and Redundancy of Profilin 1 and 2 Function in Brain Development and Neuronal Structure

Cells ◽  
2021 ◽  
Vol 10 (9) ◽  
pp. 2310
Author(s):  
Marina Di Domenico ◽  
Melanie Jokwitz ◽  
Walter Witke ◽  
Pietro Pilo Boyl
Keyword(s):  
Actin Polymerization ◽  
Conditional Knockout ◽  
Brain Morphology ◽  
Actin Dynamics ◽  
Neuronal Structure ◽  
Knockout Mouse Model ◽  
Conditional Knockout Mouse ◽  
Neuronal Stem Cell ◽  
Neuronal Precursors ◽  
Redundant Functions

Profilin functions have been discussed in numerous cellular processes, including actin polymerization. One puzzling aspect is the concomitant expression of more than one profilin isoform in most tissues. In neuronal precursors and in neurons, profilin 1 and profilin 2 are co-expressed, but their specific and redundant functions in brain morphogenesis are still unclear. Using a conditional knockout mouse model to inactivate both profilins in the developing CNS, we found that threshold levels of profilin are necessary for the maintenance of the neuronal stem-cell compartment and the generation of the differentiated neurons, irrespective of the specific isoform. During embryonic development, profilin 1 is more abundant than profilin 2; consequently, modulation of profilin 1 levels resulted in a more severe phenotype than depletion of profilin 2. Interestingly, the relevance of the isoforms was reversed in the postnatal brain. Morphology of mature neurons showed a stronger dependence on profilin 2, since this is the predominant isoform in neurons. Our data highlight redundant functions of profilins in neuronal precursor expansion and differentiation, as well as in the maintenance of pyramidal neuron dendritic arborization. The specific profilin isoform is less relevant; however, a threshold profilin level is essential. We propose that the common activity of profilin 1 and profilin 2 in actin dynamics is responsible for the observed compensatory effects.

scholarly journals A Conditional Knockout Mouse Model Reveals That Calponin-3 Is Dispensable for Early B Cell Development

PLoS ONE ◽  
2015 ◽  
Vol 10 (6) ◽  
pp. e0128385 ◽  
Author(s):  
Alexandra Flemming ◽  
Qi-Quan Huang ◽  
Jian-Ping Jin ◽  
Hassan Jumaa ◽  
Sebastian Herzog
Keyword(s):  
Mouse Model ◽  
B Cell ◽  
Knockout Mouse ◽  
Cell Development ◽  
B Cell Development ◽  
Conditional Knockout ◽  
Knockout Mouse Model ◽  
Conditional Knockout Mouse

scholarly journals A dual role for integrin-linked kinase in platelets: regulating integrin function and α-granule secretion

Blood ◽  
2008 ◽  
Vol 112 (12) ◽  
pp. 4523-4531 ◽  
Author(s):  
Katherine L. Tucker ◽  
Tanya Sage ◽  
Joanne M. Stevens ◽  
Peter A. Jordan ◽  
Sarah Jones ◽  
...  
Keyword(s):  
Thrombus Formation ◽  
Dense Granule ◽  
Conditional Knockout ◽  
Knockout Mouse Model ◽  
Conditional Knockout Mouse ◽  
Fibrinogen Binding ◽  
Integrin Linked Kinase ◽  
Dense Granule Secretion ◽  
Granule Secretion

Abstract Integrin-linked kinase (ILK) has been implicated in the regulation of a range of fundamental biological processes such as cell survival, growth, differentiation, and adhesion. In platelets ILK associates with β1- and β3-containing integrins, which are of paramount importance for the function of platelets. Upon stimulation of platelets this association with the integrins is increased and ILK kinase activity is up-regulated, suggesting that ILK may be important for the coordination of platelet responses. In this study a conditional knockout mouse model was developed to examine the role of ILK in platelets. The ILK-deficient mice showed an increased bleeding time and volume, and despite normal ultrastructure the function of ILK-deficient platelets was decreased significantly. This included reduced aggregation, fibrinogen binding, and thrombus formation under arterial flow conditions. Furthermore, although early collagen stimulated signaling such as PLCγ2 phosphorylation and calcium mobilization were unaffected in ILK-deficient platelets, a selective defect in α-granule, but not dense-granule, secretion was observed. These results indicate that as well as involvement in the control of integrin affinity, ILK is required for α-granule secretion and therefore may play a central role in the regulation of platelet function.

scholarly journals In VitroSystem for Differentiating Pluripotent Neural Crest Cells into Smooth Muscle Cells

1998 ◽  
Vol 273 (11) ◽  
pp. 5993-5996 ◽  
Author(s):  
Mukesh K. Jain ◽  
Matthew D. Layne ◽  
Masafumi Watanabe ◽  
Michael T. Chin ◽  
Mark W. Feinberg ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Neural Crest ◽  
Neural Crest Cells ◽  
Muscle Cells

scholarly journals Hormone-Responsive BMP Signaling Expands Myoepithelial Cell Lineages and Prevents Alveolar Precocity in Mammary Gland

2021 ◽  
Vol 9 ◽  
Author(s):  
Chunlei Shao ◽  
Pengbo Lou ◽  
Ruiqi Liu ◽  
Xueyun Bi ◽  
Guilin Li ◽  
...  
Keyword(s):  
Mammary Gland ◽  
Myoepithelial Cells ◽  
Bmp Signaling ◽  
Conditional Knockout ◽  
Signaling Mechanism ◽  
Knockout Mouse Model ◽  
Conditional Knockout Mouse ◽  
Morphogenetic Protein ◽  
Organ Systems ◽  
Mammary Stem

Myoepithelial and luminal cells synergistically expand in the mammary gland during pregnancy, and this process is precisely governed by hormone-related signaling pathways. The bone morphogenetic protein (BMP) signaling pathway is now known to play crucial roles in all organ systems. However, the functions of BMP signaling in the mammary gland remain unclear. Here, we found that BMPR1a is upregulated by hormone-induced Sp1 at pregnancy. Using a doxycycline (Dox)-inducible BMPR1a conditional knockout mouse model, we demonstrated that loss of BMPR1a in myoepithelium results in compromised myoepithelial integrity, reduced mammary stem cells and precocious alveolar differentiation during pregnancy. Mechanistically, BMPR1a regulates the expression of p63 and Slug, two key regulators of myoepithelial maintenance, through pSmad1/5-Smad4 complexes, and consequently activate P-cadherin during pregnancy. Furthermore, we observed that loss of BMPR1a in myoepithelium results in the upregulation of a secreted protein Spp1 that could account for the precocious alveolar differentiation in luminal layer, suggesting a defective basal-to-luminal paracrine signaling mechanism. Collectively, these findings identify a novel role of BMP signaling in maintaining the identity of myoepithelial cells and suppressing precocious alveolar formation.

scholarly journals A Homeostatic Shift Facilitates Endoplasmic Reticulum Proteostasis through Transcriptional Integration of Proteostatic Stress Response Pathways

2016 ◽  
Vol 37 (4) ◽  
Author(s):  
Liam Baird ◽  
Tadayuki Tsujita ◽  
Eri H. Kobayashi ◽  
Ryo Funayama ◽  
Takeshi Nagashima ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Transcriptional Regulation ◽  
Ubiquitin Proteasome System ◽  
Conditional Knockout ◽  
Protein Homeostasis ◽  
Knockout Mouse Model ◽  
Conditional Knockout Mouse ◽  
Wide Range ◽  
Ubiquitin Proteasome ◽  
Inducible Systems

ABSTRACT Eukaryotic cells maintain protein homeostasis through the activity of multiple basal and inducible systems, which function in concert to allow cells to adapt to a wide range of environmental conditions. Although the transcriptional programs regulating individual pathways have been studied in detail, it is not known how the different pathways are transcriptionally integrated such that a deficiency in one pathway can be compensated by a change in an auxiliary response. One such pathway that plays an essential role in many proteostasis responses is the ubiquitin-proteasome system, which functions to degrade damaged, unfolded, or short half-life proteins. Transcriptional regulation of the proteasome is mediated by the transcription factor Nrf1. Using a conditional knockout mouse model, we found that Nrf1 regulates protein homeostasis in the endoplasmic reticulum (ER) through transcriptional regulation of the ER stress sensor ATF6. In Nrf1 conditional-knockout mice, a reduction in proteasome activity is accompanied by an ATF6-dependent downregulation of the endoplasmic reticulum-associated degradation machinery, which reduces the substrate burden on the proteasome. This indicates that Nrf1 regulates a homeostatic shift through which proteostasis in the endoplasmic reticulum and cytoplasm are coregulated based on a cell's ability to degrade proteins.

Fgfr1 conditional-knockout in neural crest cells induces heterotopic chondrogenesis and osteogenesis in mouse frontal bones

2018 ◽  
Vol 52 (3) ◽  
pp. 156-163
Author(s):  
Mariko Kawai ◽  
David Herrmann ◽  
Alisa Fuchs ◽  
Shuofei Cheng ◽  
Anna Ferrer-Vaquer ◽  
...  
Keyword(s):  
Neural Crest ◽  
Neural Crest Cells ◽  
Conditional Knockout
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