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

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.

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Expression pattern of Motch, a mouse homolog of Drosophila Notch, suggests an important role in early postimplantation mouse development

Development ◽

10.1242/dev.115.3.737 ◽

1992 ◽

Vol 115 (3) ◽

pp. 737-744 ◽

Cited By ~ 22

Author(s):

F.F. Del Amo ◽

D.E. Smith ◽

P.J. Swiatek ◽

M. Gendron-Maguire ◽

R.J. Greenspan ◽

...

Keyword(s):

Cell Fate ◽

Mouse Embryo ◽

Transmembrane Protein ◽

Neuronal Cell ◽

Cell Types ◽

Drosophila Embryo ◽

Mouse Development ◽

Cell Fate Decisions ◽

Early Mouse ◽

Partial Cdna Clone

The Notch gene of Drosophila encodes a large transmembrane protein involved in cell-cell interactions and cell fate decisions in the Drosophila embryo. To determine if a gene homologous to Drosophila Notch plays a role in early mouse development, we screened a mouse embryo cDNA library with probes from the Xenopus Notch homolog, Xotch. A partial cDNA clone encoding the mouse Notch homolog, which we have termed Motch, was used to analyze expression of the Motch gene. Motch transcripts were detected in a wide variety of adult tissues, which included derivatives of all three germ layers. Differentiation of P19 embryonal carcinoma cells into neuronal cell types resulted in increased expression of Motch RNA. In the postimplantation mouse embryo Motch transcripts were first detected in mesoderm at 7.5 days post coitum (dpc). By 8.5 dpc, transcript levels were highest in presomitic mesoderm, mesenchyme and endothelial cells, while much lower levels were detected in neuroepithelium. In contrast, at 9.5 dpc, neuroepithelium was a major site of Motch expression. Transcripts were also abundant in cell types derived from neural crest. These data suggest that the Motch gene plays multiple roles in patterning and differentiation of the early postimplantation mouse embryo.

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

Development ◽

10.1242/dev.127.23.5191 ◽

2000 ◽

Vol 127 (23) ◽

pp. 5191-5201 ◽

Cited By ~ 3

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.

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

eLife ◽

10.7554/elife.46703 ◽

2019 ◽

Vol 8 ◽

Cited By ~ 2

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.

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Pointed, an ETS domain transcription factor, negatively regulates the EGF receptor pathway in Drosophila oogenesis

Development ◽

10.1242/dev.122.12.3745 ◽

1996 ◽

Vol 122 (12) ◽

pp. 3745-3754 ◽

Cited By ~ 10

Author(s):

A.M. Morimoto ◽

K.C. Jordan ◽

K. Tietze ◽

J.S. Britton ◽

E.M. O'Neill ◽

...

Keyword(s):

Transcription Factor ◽

Cell Fate ◽

Egf Receptor ◽

Follicle Cell ◽

Follicle Cells ◽

Dorsal Region ◽

Epidermal Growth ◽

Ets Domain ◽

Ets Transcription Factor ◽

Midline Cells

Spatially regulated activation of the Drosophila epidermal growth factor (EGF) receptor by its ligand, Gurken, is required for establishment of the dorsal/ventral axis of the oocyte and embryo. During mid-oogenesis, Gurken is concentrated at the dorsal-anterior of the oocyte and is thought to activate the EGF receptor pathway in adjacent follicle cells. In response to this signal, dorsal follicle cell fate is determined. These cells further differentiate into either appendage-producing or midline cells, resulting in patterning in the dorsal follicle cell layer. We show here that Pointed, an ETS transcription factor, is required in dorsal follicle cells for this patterning. Loss of pointed results in the loss of midline cells and an excess of appendage-forming cells, a phenotype associated with overactivation of the EGF receptor pathway in the dorsal region. Overexpression of pointed leads to a phenotype similar to that generated by loss of the EGF receptor pathway. This suggests that Pointed normally down-regulates EGF receptor signaling in the midline to generate patterning in the dorsal region. Interestingly, pointed expression is induced by the EGF receptor pathway. These data indicate a novel antagonistic function for Pointed in oogenesis; in response to activation of the EGF receptor, pointed is expressed and negatively regulates the EGF receptor pathway, possibly by integrating information from a second pathway.

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Development in the Mammalian Auditory System Depends on Transcription Factors

International Journal of Molecular Sciences ◽

10.3390/ijms22084189 ◽

2021 ◽

Vol 22 (8) ◽

pp. 4189

Author(s):

Karen L. Elliott ◽

Gabriela Pavlínková ◽

Victor V. Chizhikov ◽

Ebenezer N. Yamoah ◽

Bernd Fritzsch

Keyword(s):

Transcription Factors ◽

Cell Fate ◽

Auditory System ◽

Hair Cells ◽

System Development ◽

Neuronal Cell ◽

Spiral Ganglion Neuron ◽

Cochlear Hair Cells ◽

Cochlear Nuclei ◽

Bhlh Genes

We review the molecular basis of several transcription factors (Eya1, Sox2), including the three related genes coding basic helix–loop–helix (bHLH; see abbreviations) proteins (Neurog1, Neurod1, Atoh1) during the development of spiral ganglia, cochlear nuclei, and cochlear hair cells. Neuronal development requires Neurog1, followed by its downstream target Neurod1, to cross-regulate Atoh1 expression. In contrast, hair cells and cochlear nuclei critically depend on Atoh1 and require Neurod1 expression for interactions with Atoh1. Upregulation of Atoh1 following Neurod1 loss changes some vestibular neurons’ fate into “hair cells”, highlighting the significant interplay between the bHLH genes. Further work showed that replacing Atoh1 by Neurog1 rescues some hair cells from complete absence observed in Atoh1 null mutants, suggesting that bHLH genes can partially replace one another. The inhibition of Atoh1 by Neurod1 is essential for proper neuronal cell fate, and in the absence of Neurod1, Atoh1 is upregulated, resulting in the formation of “intraganglionic” HCs. Additional genes, such as Eya1/Six1, Sox2, Pax2, Gata3, Fgfr2b, Foxg1, and Lmx1a/b, play a role in the auditory system. Finally, both Lmx1a and Lmx1b genes are essential for the cochlear organ of Corti, spiral ganglion neuron, and cochlear nuclei formation. We integrate the mammalian auditory system development to provide comprehensive insights beyond the limited perception driven by singular investigations of cochlear neurons, cochlear hair cells, and cochlear nuclei. A detailed analysis of gene expression is needed to understand better how upstream regulators facilitate gene interactions and mammalian auditory system development.

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Notch signaling coordinates ommatidial rotation in the Drosophila eye via transcriptional regulation of the EGF-Receptor ligand Argos

Scientific Reports ◽

10.1038/s41598-019-55203-w ◽

2019 ◽

Vol 9 (1) ◽

Author(s):

Yildiz Koca ◽

Benjamin E. Housden ◽

William J. Gault ◽

Sarah J. Bray ◽

Marek Mlodzik

Keyword(s):

Notch Signaling ◽

Cell Fate ◽

Planar Cell Polarity ◽

Egf Receptor ◽

Control Cell ◽

Loss Of Function ◽

Egfr Signaling ◽

Specific Expression ◽

Egfr Signaling Pathway ◽

Ommatidial Rotation

AbstractIn all metazoans, a small number of evolutionarily conserved signaling pathways are reiteratively used during development to orchestrate critical patterning and morphogenetic processes. Among these, Notch (N) signaling is essential for most aspects of tissue patterning where it mediates the communication between adjacent cells to control cell fate specification. In Drosophila, Notch signaling is required for several features of eye development, including the R3/R4 cell fate choice and R7 specification. Here we show that hypomorphic alleles of Notch, belonging to the Nfacet class, reveal a novel phenotype: while photoreceptor specification in the mutant ommatidia is largely normal, defects are observed in ommatidial rotation (OR), a planar cell polarity (PCP)-mediated cell motility process. We demonstrate that during OR Notch signaling is specifically required in the R4 photoreceptor to upregulate the transcription of argos (aos), an inhibitory ligand to the epidermal growth factor receptor (EGFR), to fine-tune the activity of EGFR signaling. Consistently, the loss-of-function defects of Nfacet alleles and EGFR-signaling pathway mutants are largely indistinguishable. A Notch-regulated aos enhancer confers R4 specific expression arguing that aos is directly regulated by Notch signaling in this context via Su(H)-Mam-dependent transcription.

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The Sox-domain containing geneDichaete/fish-hookacts in concert withvndandindto regulate cell fate in theDrosophilaneuroectoderm

Development ◽

10.1242/dev.129.5.1165 ◽

2002 ◽

Vol 129 (5) ◽

pp. 1165-1174 ◽

Cited By ~ 4

Author(s):

Guoyan Zhao ◽

James B. Skeath

Keyword(s):

Cell Fate ◽

Nerve Cord ◽

Double Mutant ◽

Ventral Nerve Cord ◽

Egf Receptor ◽

Dorsoventral Axis ◽

Mutant Analysis ◽

Evolutionarily Conserved ◽

Specific Manner ◽

Important Regulator

In the Drosophila embryonic central nervous system, neural stem cells, called neuroblasts, acquire fates in a position-specific manner. Recent work has identified a set of genes that functions along the dorsoventral axis to enable neuroblasts that develop in different dorsoventral domains to acquire distinct fates. These genes include the evolutionarily conserved transcription factors ventral nerve cord defective and intermediate neuroblasts defective, as well as the Drosophila EGF receptor. We show that the Sox-domain-containing gene Dichaete/fish-hook also plays a crucial role to pattern the neuroectoderm along the DV axis. Dichaete is expressed in the medial and intermediate columns of the neuroectoderm, and mutant analysis indicates that Dichaete regulates cell fate and neuroblast formation in these domains. Molecular epistasis tests, double mutant analysis and dosage-sensitive interactions demonstrate that during these processes, Dichaete functions in parallel with ventral nerve cord defective and intermediate neuroblasts defective, and downstream of EGF receptor signaling to mediate its effect on development. These results identify Dichaete as an important regulator of dorsoventral pattern in the neuroectoderm, and indicate that Dichaete acts in concert with ventral nerve cord defective and intermediate neuroblasts defective to regulate pattern and cell fate in the neuroectoderm.

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The Drosophila orphan nuclear receptor seven-up requires the Ras pathway for its function in photoreceptor determination

Development ◽

10.1242/dev.121.1.225 ◽

1995 ◽

Vol 121 (1) ◽

pp. 225-235 ◽

Cited By ~ 3

Author(s):

G. Begemann ◽

A.M. Michon ◽

L. vd Voorn ◽

R. Wepf ◽

M. Mlodzik

Keyword(s):

Cell Fate ◽

Nuclear Receptor ◽

Egf Receptor ◽

Cell Transformation ◽

Orphan Nuclear Receptor ◽

Loss Of Function ◽

Cone Cell ◽

Ras Pathway ◽

Protein Levels ◽

Cone Cells

The Drosophila seven-up (svp) gene specifies outer photoreceptor cell fate in eye development and encodes an orphan nuclear receptor with two isoforms. Transient expression under the sevenless enhancer of either svp isoform leads to a dosage-dependent transformation of cone cells into R7 photoreceptors, and at a lower frequency, R7 cells into outer photoreceptors. To investigate the cellular pathways involved, we have taken advantage of the dosage sensitivity and screened for genes that modify this svp-induced phenotype. We show that an active Ras pathway is essential for the function of both Svp isoforms. Loss-of-function mutations in components of the Ras signal transduction cascade act as dominant suppressors of the cone cell transformation, whilst loss-of-function mutations in negative regulators of Ras-activity act as dominant enhancers. Furthermore, Svp-mediated transformation of cone cells to outer photoreceptors, reminiscent of its wild-type function in specifying R3/4 and R1/6 identity, requires an activated Ras pathway in the same cells, or alternatively dramatic increase in ectopic Svp protein levels. Our results indicate that svp is only fully functional in conjunction with activated Ras. Since we find that mutations in the Egf-receptor are also among the strongest suppressors of svp-mediated cone cell transformation, we propose that the Ras activity in cone cells is due to low level Egfr signaling. Several models that could account for the observed svp regulation by the Ras pathway are discussed.

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An activity gradient of decapentaplegic is necessary for the specification of dorsal pattern elements in the Drosophila embryo

Development ◽

10.1242/dev.117.2.807 ◽

1993 ◽

Vol 117 (2) ◽

pp. 807-822 ◽

Cited By ~ 47

Author(s):

K.A. Wharton ◽

R.P. Ray ◽

W.M. Gelbart

Keyword(s):

Cell Fate ◽

Gene Dosage ◽

Early Embryo ◽

Drosophila Embryo ◽

Cell Fates ◽

Gene Encoding ◽

In The Wild ◽

Intercellular Signalling ◽

Overlapping Domains ◽

Dorsal Pattern

decapentaplegic (dpp) is a zygotically expressed gene encoding a TGF-beta-related ligand that is necessary for dorsal-ventral patterning in the Drosophila embryo. We show here that dpp is an integral part of a gradient that specifies many different cell fates via intercellular signalling. There is a graded requirement for dpp activity in the early embryo: high levels of dpp activity specify the amnioserosa, while progressively lower levels specify dorsal and lateral ectoderm. This potential for dpp to specify cell fate is highly dosage sensitive. In the wild-type embryo, increasing the gene dosage of dpp can shift cell fates along the dorsal-ventral axis. Furthermore, in mutant embryos, in which only a subset of the dorsal-ventral pattern elements are represented, increasing the gene dosage of dpp can specifically transform those pattern elements into more dorsal ones. We present evidence that the zygotic dpp gradient and the maternal dorsal gradient specify distinct, non-overlapping domains of the dorsal-ventral pattern.

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EGF receptor signaling induces pointed P1 transcription and inactivates Yan protein in the Drosophila embryonic ventral ectoderm

Development ◽

10.1242/dev.122.11.3355 ◽

1996 ◽

Vol 122 (11) ◽

pp. 3355-3362 ◽

Cited By ~ 21

Author(s):

L. Gabay ◽

H. Scholz ◽

M. Golembo ◽

A. Klaes ◽

B.Z. Shilo ◽

...

Keyword(s):

Transcription Factors ◽

Target Genes ◽

Egf Receptor ◽

Protein A ◽

Drosophila Embryo ◽

Cell Fates ◽

Secondary Target ◽

Graded Activity ◽

Definition Of

The induction of different cell fates along the dorsoventral axis of the Drosophila embryo requires a graded activity of the EGF receptor tyrosine kinase (DER). Here we have identified primary and secondary target genes of DER, which mediate the determination of discrete ventral cell fates. High levels of DER activation in the ventralmost cells trigger expression of the transcription factors encoded by ventral nervous system defective (vnd) and pointed P1 (pntPl). Concomitant with the induction of pntP1, high levels of DER activity lead to inactivation of the Yan protein, a transcriptional repressor of Pointed-target genes. These two antagonizing transcription factors subsequently control the expression of secondary target genes such as otd, argos and tartan. The simultaneous effects of the DER pathway on pntP1 induction and Yan inactivation may contribute to the definition of the border of the ventralmost cell fates.

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