In the Absence of Sonic Hedgehog, p53 Induces Apoptosis and Inhibits Retinal Cell Proliferation, Cell-Cycle Exit and Differentiation in Zebrafish

Cell diversity in multicellular organisms relies on coordination between cell proliferation and the acquisition of cell identity. The equilibrium between these two processes is essential to assure the correct number of determined cells at a given time at a given place. Using genetic approaches and correlative microscopy, we show that Tramtrack-69 (Ttk69, a Broad-complex, Tramtrack and Bric-à-brac - Zinc Finger (BTB-ZF) transcription factor ortholog of the human promyelocytic leukemia zinc finger factor) plays an essential role in controlling this balance. In the Drosophila bristle cell lineage, which produces the external sensory organs composed by a neuron and accessory cells, we show that ttk69 loss-of-function leads to supplementary neural-type cells at the expense of accessory cells. Our data indicate that Ttk69 (1) promotes cell cycle exit of newborn terminal cells by downregulating CycE, the principal cyclin involved in S-phase entry, and (2) regulates cell-fate acquisition and terminal differentiation, by downregulating the expression of hamlet and upregulating that of Suppressor of Hairless, two transcription factors involved in neural-fate acquisition and accessory cell differentiation, respectively. Thus, Ttk69 plays a central role in shaping neural cell lineages by integrating molecular mechanisms that regulate progenitor cell cycle exit and cell-fate commitment.

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Heterochronic misexpression of Ascl1 in the Atoh7 retinal cell lineage blocks cell cycle exit

Molecular and Cellular Neuroscience ◽

10.1016/j.mcn.2013.02.004 ◽

2013 ◽

Vol 54 ◽

pp. 108-120 ◽

Cited By ~ 12

Author(s):

Robert B. Hufnagel ◽

Amy N. Riesenberg ◽

Malgorzata Quinn ◽

Joseph A. Brzezinski ◽

Tom Glaser ◽

...

Keyword(s):

Cell Cycle ◽

Cell Lineage ◽

Retinal Cell ◽

Cell Cycle Exit

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β-Arrestin-1 links mitogenic sonic hedgehog signaling to the cell cycle exit machinery in neural precursors

Cell Cycle ◽

10.4161/cc.9.19.13325 ◽

2010 ◽

Vol 9 (19) ◽

pp. 4013-4024 ◽

Cited By ~ 14

Author(s):

Susana R. Parathath ◽

Lori Anne Mainwaring ◽

Africa Fernandez-L ◽

Cemile G. Guldal ◽

Zaher Nahlé ◽

...

Keyword(s):

Cell Cycle ◽

Sonic Hedgehog ◽

Hedgehog Signaling ◽

Cell Cycle Exit ◽

Sonic Hedgehog Signaling ◽

Neural Precursors

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N-cadherin–mediated cell adhesion restricts cell proliferation in the dorsal neural tube

Molecular Biology of the Cell ◽

10.1091/mbc.e10-08-0675 ◽

2011 ◽

Vol 22 (9) ◽

pp. 1505-1515 ◽

Cited By ~ 18

Author(s):

Kavita Chalasani ◽

Rachel M. Brewster

Keyword(s):

Cell Cycle ◽

Cell Proliferation ◽

Neural Tube ◽

Neural Progenitor ◽

Neural Progenitors ◽

Cell Cycle Exit ◽

Dorsal Neural Tube ◽

Binding Partners ◽

Hh Signaling ◽

Cell Cycle Length

Neural progenitors are organized as a pseudostratified epithelium held together by adherens junctions (AJs), multiprotein complexes composed of cadherins and α- and β-catenin. Catenins are known to control neural progenitor division; however, it is not known whether they function in this capacity as cadherin binding partners, as there is little evidence that cadherins themselves regulate neural proliferation. We show here that zebrafish N-cadherin (N-cad) restricts cell proliferation in the dorsal region of the neural tube by regulating cell-cycle length. We further reveal that N-cad couples cell-cycle exit and differentiation, as a fraction of neurons are mitotic in N-cad mutants. Enhanced proliferation in N-cad mutants is mediated by ligand-independent activation of Hedgehog (Hh) signaling, possibly caused by defective ciliogenesis. Furthermore, depletion of Hh signaling results in the loss of junctional markers. We therefore propose that N-cad restricts the response of dorsal neural progenitors to Hh and that Hh signaling limits the range of its own activity by promoting AJ assembly. Taken together, these observations emphasize a key role for N-cad–mediated adhesion in controlling neural progenitor proliferation. In addition, these findings are the first to demonstrate a requirement for cadherins in synchronizing cell-cycle exit and differentiation and a reciprocal interaction between AJs and Hh signaling.

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HES1 is a novel downstream modifier of the SHH-GLI3 Axis in the development of preaxial polydactyly

PLoS Genetics ◽

10.1371/journal.pgen.1009982 ◽

2021 ◽

Vol 17 (12) ◽

pp. e1009982

Author(s):

Deepika Sharma ◽

Anthony J. Mirando ◽

Abigail Leinroth ◽

Jason T. Long ◽

Courtney M. Karner ◽

...

Keyword(s):

Cell Cycle ◽

Cell Proliferation ◽

Sonic Hedgehog ◽

Mesenchymal Cell ◽

Digit Number ◽

Preaxial Polydactyly ◽

Molecular Approaches ◽

Downstream Effector ◽

Signaling Axis

Sonic Hedgehog/GLI3 signaling is critical in regulating digit number, such that Gli3-deficiency results in polydactyly and Shh-deficiency leads to digit number reductions. SHH/GLI3 signaling regulates cell cycle factors controlling mesenchymal cell proliferation, while simultaneously regulating Grem1 to coordinate BMP-induced chondrogenesis. SHH/GLI3 signaling also coordinates the expression of additional genes, however their importance in digit formation remain unknown. Utilizing genetic and molecular approaches, we identified HES1 as a downstream modifier of the SHH/GLI signaling axis capable of inducing preaxial polydactyly (PPD), required for Gli3-deficient PPD, and capable of overcoming digit number constraints of Shh-deficiency. Our data indicate that HES1, a direct SHH/GLI signaling target, induces mesenchymal cell proliferation via suppression of Cdkn1b, while inhibiting chondrogenic genes and the anterior autopod boundary regulator, Pax9. These findings establish HES1 as a critical downstream effector of SHH/GLI3 signaling in the development of PPD.

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The multi-subunit GID/CTLH E3 ubiquitin ligase promotes cell proliferation and targets the transcription factor Hbp1 for degradation

eLife ◽

10.7554/elife.35528 ◽

2018 ◽

Vol 7 ◽

Cited By ~ 28

Author(s):

Fabienne Lampert ◽

Diana Stafa ◽

Algera Goga ◽

Martin Varis Soste ◽

Samuel Gilberto ◽

...

Keyword(s):

Cell Cycle ◽

Cell Proliferation ◽

Ubiquitin Ligase ◽

E3 Ubiquitin Ligase ◽

Hierarchical Organization ◽

Negative Regulator ◽

Cell Cycle Exit ◽

Cellular Analysis ◽

Ubiquitin Ligase Activity

In yeast, the glucose-induced degradation-deficient (GID) E3 ligase selectively degrades superfluous gluconeogenic enzymes. Here, we identified all subunits of the mammalian GID/CTLH complex and provide a comprehensive map of its hierarchical organization and step-wise assembly. Biochemical reconstitution demonstrates that the mammalian complex possesses inherent E3 ubiquitin ligase activity, using Ube2H as its cognate E2. Deletions of multiple GID subunits compromise cell proliferation, and this defect is accompanied by deregulation of critical cell cycle markers such as the retinoblastoma (Rb) tumor suppressor, phospho-Histone H3 and Cyclin A. We identify the negative regulator of pro-proliferative genes Hbp1 as a bonafide GID/CTLH proteolytic substrate. Indeed, Hbp1 accumulates in cells lacking GID/CTLH activity, and Hbp1 physically interacts and is ubiquitinated in vitro by reconstituted GID/CTLH complexes. Our biochemical and cellular analysis thus demonstrates that the GID/CTLH complex prevents cell cycle exit in G1, at least in part by degrading Hbp1.

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HES1 is a Critical Mediator of the SHH-GLI3 Axis in Regulating Digit Number

10.1101/2020.06.17.158501 ◽

2020 ◽

Author(s):

Deepika Sharma ◽

Anthony J. Mirando ◽

Abigail Leinroth ◽

Jason T. Long ◽

Courtney M. Karner ◽

...

Keyword(s):

Cell Cycle ◽

Cell Proliferation ◽

Sonic Hedgehog ◽

Transcriptional Regulator ◽

Mesenchymal Cell ◽

Digit Number ◽

Preaxial Polydactyly ◽

Molecular Approaches ◽

Comprehensive Framework ◽

Anterior Posterior

ABSTRACTSonic Hedgehog/GLI3 signaling is critical in regulating digit number, such that Gli3-deficiency results in polydactyly and Shh-deficiency leads to digit number reductions. Anterior-posterior SHH/GLI3 signaling gradients regulate cell cycle factors controlling mesenchymal cell proliferation, while simultaneously regulating Grem1 to coordinate BMP-induced chondrogenesis. SHH/GLI3 also coordinates the expression of additional genes, however their importance in digit formation remain unknown. Utilizing genetic and molecular approaches, we identified HES1 as a key transcriptional regulator downstream of SHH/GLI signaling capable of inducing preaxial polydactyly (PPD), required for Gli3-deficient PPD, and capable of overcoming digit number constraints of Shh-deficiency. Our data indicate that HES1, a direct SHH/GLI signaling target, induces mesenchymal cell proliferation via suppression of Cdkn1b, while inhibiting chondrogenic genes and the anterior autopod boundary regulator, Pax9. These findings fill gaps in knowledge regarding digit number and patterning, while creating a comprehensive framework for our molecular understanding of critical mediators of SHH/GLI3 signaling.

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Auditory ganglion source of Sonic hedgehog regulates timing of cell cycle exit and differentiation of mammalian cochlear hair cells

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1222341110 ◽

2013 ◽

Vol 110 (34) ◽

pp. 13869-13874 ◽

Cited By ~ 48

Author(s):

Jinwoong Bok ◽

Colleen Zenczak ◽

Chan Ho Hwang ◽

Doris K. Wu

Keyword(s):

Cell Cycle ◽

Sonic Hedgehog ◽

Hair Cells ◽

Cell Cycle Exit ◽

Cochlear Hair Cells

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Only Akt1 Is Required for Proliferation, while Akt2 Promotes Cell Cycle Exit through p21 Binding

Molecular and Cellular Biology ◽

10.1128/mcb.00201-06 ◽

2006 ◽

Vol 26 (22) ◽

pp. 8267-8280 ◽

Cited By ~ 112

Author(s):

Lisa Héron-Milhavet ◽

Celine Franckhauser ◽

Vanessa Rana ◽

Cyril Berthenet ◽

Daniel Fisher ◽

...

Keyword(s):

Cell Cycle ◽

Cell Proliferation ◽

Mammalian Cells ◽

Cell Cycle Progression ◽

Specific Interaction ◽

Cyclin A ◽

Cell Cycle Exit ◽

Cycle Progression ◽

Negative Effect

ABSTRACT Protein kinase B (PKB/Akt) is an important modulator of insulin signaling, cell proliferation, and survival. Using small interfering RNA duplexes in nontransformed mammalian cells, we show that only Akt1 is essential for cell proliferation, while Akt2 promotes cell cycle exit. Silencing Akt1 resulted in decreased cyclin A levels and inhibition of S-phase entry, effects not seen with Akt2 knockdown and specifically rescued by microinjection of Akt1, not Akt2. In differentiating myoblasts, Akt2 knockout prevented myoblasts from exiting the cell cycle and showed sustained cyclin A expression. In contrast, overexpression of Akt2 reduced cyclin A and hindered cell cycle progression in M-G1 with increased nuclear p21. p21 is a major target in the differential effects of Akt isoforms, with endogenous Akt2 and not Akt1 binding p21 in the nucleus and increasing its level. Accordingly, Akt2 knockdown cells, and not Akt1 knockdown cells, showed reduced levels of p21. A specific Akt2/p21 interaction can be reproduced in vitro, and the Akt2 binding site on p21 is similar to that in cyclin A spanning T145 to T155, since (i) prior incubation with cyclin A prevents Akt2 binding, (ii) T145 phosphorylation on p21 by Akt1 prevents Akt2 binding, and (iii) binding Akt2 prevents phosphorylation of p21 by Akt1. These data show that specific interaction of the Akt2 isoform with p21 is key to its negative effect on normal cell cycle progression.

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The BTB-ZF transcription factor Tramtrack69 shapes neural cell lineages by coordinating cell proliferation and cell fate

10.1101/338285 ◽

2018 ◽

Author(s):

Françoise Simon ◽

Anne Ramat ◽

Sophie Louvet-Vallée ◽

Jérôme Lacoste ◽

Angélique Burg ◽

...

Keyword(s):

Cell Cycle ◽

Cell Proliferation ◽

Transcription Factor ◽

Cell Fate ◽

Progenitor Cell ◽

Molecular Mechanisms ◽

Neural Cell ◽

Cell Cycle Exit ◽

Cell Lineages ◽

Accessory Cells

AbstractCell diversity in multicellular organisms relies on coordination between cell proliferation and the acquisition of cell identity. The equilibrium between these two processes is essential to assure the correct number of determined cells at a given time at a given place. Here, we show that Tramtrack-69 (Ttk69, a BTB-ZF transcription factor ortholog of the human PLZF factor) plays an essential role in controlling this balance. In theDrosophilabristle cell lineage, producing the external sensory organs composed by a neuron and accessory cells, we show thatttk69loss of function leads to supplementary neural-type cells at the expense of accessory cells. Our data indicate that Ttk69 (1) promotes cell-cycle exit of newborn terminal cells by downregulatingcycE, the principal cyclin involved in S-phase entry and (2) regulates cell fate acquisition and terminal differentiation by downregulating the expression ofhamletand upregulating that ofSuppressor of Hairless, two transcription factors involved in neural-fate acquisition and accessory-cell differentiation, respectively. Thus, Ttk69 plays a central role in shaping neural cell lineages by integrating molecular mechanisms that regulate progenitor cell-cycle exit and cell-fate commitment.Summary statementTramtrack-69, a transcription factor orthologous to the human tumor-suppressor PLZF, plays a central role in precursor cell lineages by integrating molecular mechanisms that regulate progenitor cell-cycle exit and cell-fate determination.

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