The AP-2 transcription factor is required for joint formation and cell survival in Drosophila leg development

Flies mutant for the Drosophila homologue of the mammalian transcription factor AP-2 show a severe reduction in leg length and fail to develop joint structures. Presumptive joint cells express dAP-2 in response to Notch signaling. dAP-2 is required for joint cell differentiation and can induce formation of supernumerary joints when misexpressed. Although dAP-2 is expressed only in presumptive joint cells, its activity is required to support cell survival in the entire leg segment. Taken together, our data indicate that dAP-2 is an important mediator of Notch activity in leg development.

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The bHLH-PAS Transcription Factor Dysfusion Regulates Tarsal Joint Formation in Response to Notch Activity during Drosophila Leg Development

PLoS Genetics ◽

10.1371/journal.pgen.1004621 ◽

2014 ◽

Vol 10 (10) ◽

pp. e1004621 ◽

Cited By ~ 11

Author(s):

Sergio Córdoba ◽

Carlos Estella

Keyword(s):

Transcription Factor ◽

Joint Formation ◽

Notch Activity ◽

Tarsal Joint ◽

Leg Development

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Osteopetrosis in TAK1-deficient mice owing to defective NF-κB and NOTCH signaling

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1415213112 ◽

2014 ◽

Vol 112 (1) ◽

pp. 154-159 ◽

Cited By ~ 30

Author(s):

Gaurav Swarnkar ◽

Kannan Karuppaiah ◽

Gabriel Mbalaviele ◽

Tim (Hung-Po) Chen ◽

Yousef Abu-Amer

Keyword(s):

Transcription Factor ◽

Notch Signaling ◽

Cell Survival ◽

Mechanism Of Action ◽

Crucial Role ◽

Myeloid Cells ◽

Cellular Functions ◽

Recognition Sequence ◽

Notch Intracellular Domain ◽

Deficient Mice

The MAP kinase TGFβ-activated kinase (TAK1) plays a crucial role in physiologic and pathologic cellular functions including cell survival, differentiation, apoptosis, inflammation, and oncogenesis. However, the entire repertoire of its mechanism of action has not been elucidated. Here, we found that ablation of Tak1 in myeloid cells causes osteopetrosis in mice as a result of defective osteoclastogenesis. Mechanistically, Tak1 deficiency correlated with increased NUMB-like (NUMBL) levels. Accordingly, forced expression of Numbl abrogated osteoclastogenesis whereas its deletion partially restored osteoclastogenesis and reversed the phenotype of Tak1 deficiency. Tak1 deletion also down-regulated Notch intracellular domain (NICD), but increased the levels of the transcription factor recombinant recognition sequence binding protein at Jκ site (RBPJ), consistent with NUMBL regulating notch signaling through degradation of NICD, a modulator of RBPJ. Accordingly, deletion of Rbpj partially corrected osteopetrosis in Tak1-deficient mice. Furthermore, expression of active IKK2 in RBPJ/TAK1-deficient cells significantly restored osteoclastogenesis, indicating that activation of NF-κB is essential for complete rescue of the pathway. Thus, we propose that TAK1 regulates osteoclastogenesis by integrating activation of NF-κB and derepression of NOTCH/RBPJ in myeloid cells through inhibition of NUMBL.

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Prdm16 and Notch functionally and physically interact during artery development

10.1101/2021.12.05.471275 ◽

2021 ◽

Author(s):

Manu Beerens ◽

Jore Van Wauwe ◽

Sander Craps ◽

Margo Daems ◽

KC Ashmita ◽

...

Keyword(s):

Transcription Factor ◽

Notch Signaling ◽

Circulatory System ◽

Bhlh Transcription Factor ◽

Vascular Disorders ◽

Notch Activity ◽

Related Family ◽

Downstream Effector ◽

Arterial Development

ABSTRACTRationaleProper functionality of the circulatory system requires correct arteriovenous (AV) endothelial cell (EC) differentiation. While Notch signaling and its downstream effector Hes- Related Family bHLH Transcription Factor with YRPW Motif (Hey)2 favor arterial specification, transcription factor (TF) chicken ovalbumin upstream transcription factor 2 (Coup-TFII) inhibits canonical Notch activity to induce venous identity. However, transcriptional programs that compete with Coup-TFII to orchestrate arterial specification upstream of Notch remain largely unknown. We identified positive regulatory domain-containing protein (Prdm)16 as an arterial EC- specific TF, but its role during arterial EC specification and development remains unexplored.ObjectiveTo unravel the role of Prdm16 during arterial endothelial lineage specification and artery formation.Methods and ResultsTranscriptomic data of freshly isolated arterial and venous ECs from humans and mice revealed that Prdm16 is exclusively expressed by arterial ECs throughout development. This expression pattern was independent of hemodynamic factors and conserved in zebrafish. Accordingly, loss of prdm16 in zebrafish perturbed AV endothelial specification and caused AV malformations in an EC-autonomous manner. This coincided with reduced canonical Notch activity in arterial ECs and was amplified when prdm16 and notch pathway members were concomitantly knocked down. In vitro studies further indicated that Prdm16 not only amplified Notch signaling, but also physically and functionally interacted with Hey2 to drive proper arterial specification.ConclusionWe showed that Prdm16 plays a pivotal role during arterial development through its physical and functional interaction with canonical Notch. As both Hey2 and Prdm16 have been associated with diverse vascular disorders including migraine and atherosclerosis, Prdm16 represents an attractive new target to treat these vascular disorders.

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