The Phox2b transcription factor coordinately regulates neuronal cell cycle exit and identity

Development ◽  
2000 ◽  
Vol 127 (23) ◽  
pp. 5191-5201 ◽  
Author(s):  
V. Dubreuil ◽  
M. Hirsch ◽  
A. Pattyn ◽  
J. Brunet ◽  
C. Goridis
Keyword(s):  
Cell Cycle ◽  
Transcription Factor ◽  
Cell Fate ◽  
Motor Neurons ◽  
Ventricular Zone ◽  
Ectopic Expression ◽  
Neuronal Cell ◽  
Cell Cycle Exit ◽  
Neuronal Precursors ◽  
Regulation Of Cell Cycle

In the vertebrate neural tube, cell cycle exit of neuronal progenitors is accompanied by the expression of transcription factors that define their generic and sub-type specific properties, but how the regulation of cell cycle withdrawal intersects with that of cell fate determination is poorly understood. Here we show by both loss- and gain-of-function experiments that the neuronal-subtype-specific homeodomain transcription factor Phox2b drives progenitor cells to become post-mitotic. In the absence of Phox2b, post-mitotic neuronal precursors are not generated in proper numbers. Conversely, forced expression of Phox2b in the embryonic chick spinal cord drives ventricular zone progenitors to become post-mitotic neurons and to relocate to the mantle layer. In the neurons thus generated, ectopic expression of Phox2b is sufficient to initiate a programme of motor neuronal differentiation characterised by expression of Islet1 and of the cholinergic transmitter phenotype, in line with our previous results showing that Phox2b is an essential determinant of cranial motor neurons. These results suggest that Phox2b coordinates quantitative and qualitative aspects of neurogenesis, thus ensuring that neurons of the correct phenotype are generated in proper numbers at the appropriate times and locations.

scholarly journals A Myt1 family transcription factor defines neuronal fate by repressing non-neuronal genes

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
Joo Lee ◽  
Caitlin A Taylor ◽  
Kristopher M Barnes ◽  
Ao Shen ◽  
Emerson V Stewart ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Cell Fate ◽  
Zinc Finger ◽  
Target Cell ◽  
Ectopic Expression ◽  
Neuronal Cell ◽  
Corepressor Complex ◽  
Neuronal Precursors ◽  
Neuronal Genes

Cellular differentiation requires both activation of target cell transcriptional programs and repression of non-target cell programs. The Myt1 family of zinc finger transcription factors contributes to fibroblast to neuron reprogramming in vitro. Here, we show that ztf-11 (Zinc-finger Transcription Factor-11), the sole Caenorhabditis elegans Myt1 homolog, is required for neurogenesis in multiple neuronal lineages from previously differentiated epithelial cells, including a neuron generated by a developmental epithelial-to-neuronal transdifferentiation event. ztf-11 is exclusively expressed in all neuronal precursors with remarkable specificity at single-cell resolution. Loss of ztf-11 leads to upregulation of non-neuronal genes and reduced neurogenesis. Ectopic expression of ztf-11 in epidermal lineages is sufficient to produce additional neurons. ZTF-11 functions together with the MuvB corepressor complex to suppress the activation of non-neuronal genes in neurons. These results dovetail with the ability of Myt1l (Myt1-like) to drive neuronal transdifferentiation in vitro in vertebrate systems. Together, we identified an evolutionarily conserved mechanism to specify neuronal cell fate by repressing non-neuronal genes.

scholarly journals Shaping of Drosophila Neural Cell Lineages Through Coordination of Cell Proliferation and Cell Fate by the BTB-ZF Transcription Factor Tramtrack-69

Genetics ◽  
2019 ◽  
Vol 212 (3) ◽  
pp. 773-788
Author(s):  
Françoise Simon ◽  
Anne Ramat ◽  
Sophie Louvet-Vallée ◽  
Jérôme Lacoste ◽  
Angélique Burg ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
Transcription Factor ◽  
Cell Fate ◽  
Zinc Finger ◽  
Molecular Mechanisms ◽  
Neural Cell ◽  
Cell Cycle Exit ◽  
Cell Lineages ◽  
Accessory Cells

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.

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

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.

scholarly journals Recessive PRDM13 Mutations Result in Hypogonadotropic Hypogonadism and Cerebellar Hypoplasia

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. A551-A551
Author(s):  
Roberto Oleari ◽  
Danielle Whittaker ◽  
Louise Cheryl Gregory ◽  
Basson Albert ◽  
Anna Maria Cariboni ◽  
...  
Keyword(s):  
Cell Fate ◽  
Ventricular Zone ◽  
Hypogonadotropic Hypogonadism ◽  
Ectopic Expression ◽  
Neuronal Cell ◽  
Mechanistic Explanation ◽  
Gonadal Development ◽  
Delayed Puberty ◽  
Cerebellar Hypoplasia ◽  
Pr Domain

Abstract PRDM13 (PR Domain containing 13) is a putative chromatin modifier and transcriptional regulator that functions downstream of the transcription factor PTF1A. Here, we report a novel, recessive syndrome associated with PRDM13 mutation. Patients exhibited intellectual disability, ataxia with cerebellar hypoplasia, scoliosis and delayed puberty with hypogonadotropic hypogonadism (HH). We investigated the development of hypothalamic neurons and the cerebellum in mice homozygous for a Prdm13 mutant allele. Cerebellar hypoplasia was evident, but male gonadal development appeared unaffected in these mutants. As PTF1A has been linked to early GABAergic neuronal cell fate regulation in the spinal cord, we examined GABAergic neuron progenitor development in the hypothalamus and cerebellum. A significant reduction in the number of Kisspeptin neurons in the hypothalamus and PAX2+ progenitors emerging from the cerebellar ventricular zone was observed. The latter was accompanied by ectopic expression of the glutamatergic lineage marker TLX3. Together, these findings identify PRDM13 as a critical regulator of GABAergic cell fate during neurodevelopment, providing a mechanistic explanation for the co-occurrence of HH and cerebellar hypoplasia in this syndrome. To our knowledge, this is the first evidence linking disrupted regulation of Kiss1 neurons to CHH in humans.

split ends encodes large nuclear proteins that regulate neuronal cell fate and axon extension in the Drosophila embryo

Development ◽  
2000 ◽  
Vol 127 (7) ◽  
pp. 1517-1529 ◽  
Author(s):  
B. Kuang ◽  
S.C. Wu ◽  
Y. Shin ◽  
L. Luo ◽  
P. Kolodziej
Keyword(s):  
Cell Fate ◽  
Egf Receptor ◽  
Neuronal Cell ◽  
Drosophila Embryo ◽  
Neuronal Precursors ◽  
Split Ends ◽  
Recognition Motifs ◽  
Midline Cells ◽  
Wrong Number ◽  
Nuclear Levels

split ends (spen) encodes nuclear 600 kDa proteins that contain RNA recognition motifs and a conserved C-terminal sequence. These features define a new protein family, Spen, which includes the vertebrate MINT transcriptional regulator. Zygotic spen mutants affect the growth and guidance of a subset of axons in the Drosophila embryo. Removing maternal and zygotic protein elicits cell-fate and more general axon-guidance defects that are not seen in zygotic mutants. The wrong number of chordotonal neurons and midline cells are generated, and we identify defects in precursor formation and EGF receptor-dependent inductive processes required for cell-fate specification. The number of neuronal precursors is variable in embryos that lack Spen. The levels of Suppressor of Hairless, a key transcriptional effector of Notch required for precursor formation, are reduced, as are the nuclear levels of Yan, a transcriptional repressor that regulates cell fate and proliferation downstream of the EGF receptor. We propose that Spen proteins regulate the expression of key effectors of signaling pathways required to specify neuronal cell fate and morphology.

scholarly journals Chromatin organization changes during the establishment and maintenance of the postmitotic state

2017 ◽  
Author(s):  
Yiqin Ma ◽  
Laura Buttitta
Keyword(s):  
Cell Cycle ◽  
Gene Silencing ◽  
Ectopic Expression ◽  
Terminal Differentiation ◽  
Chromatin Organization ◽  
Cell Cycle Exit ◽  
Heterochromatin Protein 1 ◽  
Developmental Potential ◽  
Close Relationship ◽  
The Face

SummaryBackgroundGenome organization changes during development as cells differentiate. Chromatin motion becomes increasingly constrained and heterochromatin clusters as cells become restricted in their developmental potential. These changes coincide with slowing of the cell cycle, which can also influence chromatin organization and dynamics. Terminal differentiation is often coupled with permanent exit from the cell cycle and existing data suggests a close relationship between a repressive chromatin structure and silencing of the cell cycle in postmitotic cells. Here we examine the relationship between chromatin organization, terminal differentiation and cell cycle exit.ResultsWe focused our studies on the Drosophila wing, where epithelial cells transition from active proliferation to a postmitotic state in a temporally controlled manner. We find there are two stages of G0 in this tissue, a flexible G0 period where cells can be induced to re-enter the cell cycle under specific genetic manipulations and a state we call “robust”, where cells become strongly refractory to cell cycle re-entry. Compromising the flexible G0 by driving ectopic expression of cell cycle activators causes a global disruption of the clustering of heterochromatin-associated histone modifications such as H3K27 trimethylation and H3K9 trimethylation, as well as their associated repressors, Polycomb and heterochromatin protein 1(HP1). However, this disruption is reversible. When cells enter a robust G0 state, even in the presence of ectopic cell cycle activity, clustering of heterochromatin associated modifications are restored. If cell cycle exit is bypassed, cells in the wing continue to terminally differentiate, but heterochromatin clustering is severely disrupted. Heterochromatin-dependent gene silencing does not appear to be required for cell cycle exit, as compromising the H3K27 methyltransferase Enhancer of zeste, and/or HP1 cannot prevent the robust cell cycle exit, even in the face of normally oncogenic cell cycle activities.ConclusionsHeterochromatin clustering during terminal differentiation is a consequence of cell cycle exit, rather than differentiation. Compromising heterochromatin-dependent gene silencing does not disrupt cell cycle exit.

scholarly journals Regulation of Cell Cycle-Specific Gene Expression through Cyclin-Dependent Kinase-Mediated Phosphorylation of the Forkhead Transcription Factor Fkh2p

2004 ◽  
Vol 24 (22) ◽  
pp. 10036-10046 ◽  
Author(s):  
Aline Pic-Taylor ◽  
Zoulfia Darieva ◽  
Brian A. Morgan ◽  
Andrew D. Sharrocks
Keyword(s):  
Cell Cycle ◽  
Transcription Factor ◽  
Specific Gene ◽  
Cyclin Dependent Kinase ◽  
Forkhead Transcription Factor ◽  
Cyclin Dependent Kinases ◽  
Regulated Expression ◽  
Dependent Protein ◽  
Cycle Dependent ◽  
Regulation Of Cell Cycle

ABSTRACT The forkhead transcription factor Fkh2p acts in a DNA-bound complex with Mcm1p and the coactivator Ndd1p to regulate cell cycle-dependent expression of the CLB2 gene cluster in Saccharomyces cerevisiae. Here, we demonstrate that Fkh2p is a target of cyclin-dependent protein kinases and that phosphorylation of Fkh2p promotes interactions between Fkh2p and the coactivator Ndd1p. These phosphorylation-dependent changes in the Fkh2p-Ndd1p complex play an important role in the cell cycle-regulated expression of the CLB2 cluster. Our data therefore identify an important regulatory target for cyclin-dependent kinases in the cell cycle and further our molecular understanding of the key cell cycle regulatory transcription factor Fkh2p.

scholarly journals Laminin β2 Chain Regulates Cell Cycle Dynamics in the Developing Retina

2022 ◽  
Vol 9 ◽  
Author(s):  
Dmitri Serjanov ◽  
Galina Bachay ◽  
Dale D. Hunter ◽  
William J. Brunken
Keyword(s):  
Cell Cycle ◽  
Cell Fate ◽  
Critical Role ◽  
Laminin Receptor ◽  
Cell Cycle Exit ◽  
Cell Fate Decisions ◽  
M Phase ◽  
Cell Cycle Dynamics ◽  
Laminin Β2

Vertebrate retinal development follows a highly stereotyped pattern, in which the retinal progenitor cells (RPCs) give rise to all retinal types in a conserved temporal sequence. Ensuring the proper control over RPC cell cycle exit and re-entry is, therefore, crucially important for the generation of properly functioning retina. In this study, we demonstrate that laminins, indispensible ECM components, at the retinal surface, regulate the mechanisms determining whether RPCs generate proliferative or post-mitotic progeny. In vivo deletion of laminin β2 in mice resulted in disturbing the RPC cell cycle dynamics, and premature cell cycle exit. Specifically, the RPC S-phase is shortened, with increased numbers of cells present in its late stages. This is followed by an accelerated G2-phase, leading to faster M-phase entry. Finally, the M-phase is extended, with RPCs dwelling longer in prophase. Addition of exogenous β2-containing laminins to laminin β2-deficient retinal explants restored the appropriate RPC cell cycle dynamics, as well as S and M-phase progression, leading to proper cell cycle re-entry. Moreover, we show that disruption of dystroglycan, a laminin receptor, phenocopies the laminin β2 deletion cell cycle phenotype. Together, our findings suggest that dystroglycan-mediated ECM signaling plays a critical role in regulating the RPC cell cycle dynamics, and the ensuing cell fate decisions.

scholarly journals Co-ordinating retinal histogenesis: early cell cycle exit enhances early cell fate determination in the Xenopus retina

Development ◽  
2002 ◽  
Vol 129 (10) ◽  
pp. 2435-2446 ◽  
Author(s):  
Shin-ichi Ohnuma ◽  
Susannah Hopper ◽  
Kevin C. Wang ◽  
Anna Philpott ◽  
William A. Harris
Keyword(s):  
Cell Cycle ◽  
Cell Fate ◽  
Kinase Inhibitor ◽  
Cell Types ◽  
Retinal Ganglion ◽  
Cell Cycle Exit ◽  
Cyclin E1 ◽  
Distinct Cell ◽  
Cyclin Kinase Inhibitor ◽  
Notch Activation

The laminar arrays of distinct cell types in the vertebrate retina are built by a histogenic process in which cell fate is correlated with birth order. To explore this co-ordination mechanistically, we altered the relative timing of cell cycle exit in the developing Xenopus retina and asked whether this affected the activity of neural determinants. We found that Xath5, a bHLH proneural gene that promotes retinal ganglion cell (RGC) fate, (Kanekar, S., Perron, M., Dorsky, R., Harris, W. A., Jan, L. Y., Jan, Y. N. and Vetter, M. L. (1997) Neuron19, 981-994), does not cause these cells to be born prematurely. To drive cells out of the cell cycle early, therefore, we misexpressed the cyclin kinase inhibitor, p27Xic1. We found that early cell cycle exit potentiates the ability of Xath5 to promote RGC fate. Conversely, the cell cycle activator, cyclin E1, which inhibits cell cycle exit, biases Xath5-expressing cells toward later neuronal fates. We found that Notch activation in this system caused cells to exit the cell cycle prematuely, and when it is misexpressed with Xath5, it also potentiates the induction of RGCs. The potentiation is counteracted by co-expression of cyclin E1. These results suggest a model of histogenesis in which the activity of factors that promote early cell cycle exit enhances the activity of factors that promote early cellular fates.

scholarly journals The transcription factor Zic4 acts as a transdifferentiation switch

2021 ◽  
Author(s):  
Matthias Christian Vogg ◽  
Jaroslav Ferenc ◽  
Wanda Christa Buzgariu ◽  
Chrystelle Perruchoud ◽  
Panagiotis Papasaikas ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Transcription Factor ◽  
Gene Regulatory Network ◽  
Cell Fate ◽  
Regulatory Network ◽  
Molecular Mechanisms ◽  
Model System ◽  
Cell Identity ◽  
Transcriptional Switch ◽  
Gene Regulatory

The molecular mechanisms that maintain cell identities and prevent transdifferentiation remain mysterious. Interestingly, both dedifferentiation and transdifferentiation are transiently reshuffled during regeneration. Therefore, organisms that regenerate readily offer a fruitful paradigm to investigate the regulation of cell fate stability. Here, we used Hydra as a model system and show that Zic4 silencing is sufficient to induce transdifferentiation of tentacle into foot cells. We identified a Wnt-controlled Gene Regulatory Network that controls a transcriptional switch of cell identity. Furthermore, we show that this switch also controls the re-entry into the cell cycle. Our data indicate that maintenance of cell fate by a Wnt-controlled GRN is a key mechanism during both homeostasis and regeneration.

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