Hox and Pbx Factors Control Retinoic Acid Synthesis during Hindbrain Segmentation

Vitobello, Antonio; Ferretti, Elisabetta; Lampe, Xavier; Vilain, Nathalie; Ducret, Sébastien; Ori, Michela; Spetz, Jean-François; Selleri, Licia; Rijli, Filippo M.

doi:10.1016/j.devcel.2011.03.011

Cited by 86 publications

(91 citation statements)

References 64 publications

(73 reference statements)

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“…It was shown recently that Raldh2 expression is under the transcriptional control of a ternary complex that includes Hox, Pbx and Meis proteins. Both Pbx1;Pbx2 and Hoxa1;Pbx1 compound mutant mice show reduced mesodermal Raldh2 expression (Vitobello et al, 2011). These authors show that HOXA1-PBX1/2-MEIS2 directly binds a regulatory element required to maintain normal Raldh2 expression.…”

Section: Kastner Et Al 1996mentioning

confidence: 70%

Retinoic acid signalling during development

2012

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Retinoic acid (RA) is a vitamin A-derived, non-peptidic, small lipophilic molecule that acts as ligand for nuclear RA receptors (RARs), converting them from transcriptional repressors to activators. The distribution and levels of RA in embryonic tissues are tightly controlled by regulated synthesis through the action of specific retinol and retinaldehyde dehydrogenases and by degradation via specific cytochrome P450s (CYP26s). Recent studies indicate that RA action involves an interplay between diffusion (morphogen-like) gradients and the establishment of signalling boundaries due to RA metabolism, thereby allowing RA to finely control the differentiation and patterning of various stem/progenitor cell populations. Here, we provide an overview of the RA biosynthesis, degradation and signalling pathways and review the main functions of this molecule during embryogenesis.

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Section: Kastner Et Al 1996mentioning

confidence: 70%

Retinoic acid signalling during development

2012

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“…Pbx proteins are regulated transcriptionally and posttranslationally by RA, which increases mRNA levels and extends protein half-lives, respectively (Qin et al, 2004). Hox and Pbx genes positively reinforce RA signaling by driving Raldh2 (Aldh1a2) expression in the developing hindbrain in a feedforward mechanism (Vitobello et al, 2011). Local RA synthesis is driven by Ahd2 and is therefore restricted to the rostrolateral mdDA area (Jacobs et al, 2007;Jacobs et al, 2011), suggesting that local RA synthesis reinforces the rostrolateral mdDA phenotype.…”

Section: Ahd2 and Cck Mark Dopaminergic Subsets That Display Differenmentioning

confidence: 99%

Specification of dopaminergic subsets involves interplay of En1 and Pitx3

et al. 2013

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Mesodiencephalic dopaminergic (mdDA) neurons control locomotion and emotion and are affected in multiple psychiatric and neurodegenerative diseases, including Parkinson’s disease (PD). The homeodomain transcription factor Pitx3 is pivotal in mdDA neuron development and loss of Pitx3 results in programming deficits in a rostrolateral subpopulation of mdDA neurons destined to form the substantia nigra pars compacta (SNc), reminiscent of the specific cell loss observed in PD. We show here that in adult mice in which the gene encoding a second homeoprotein, engrailed 1 (En1), has been deleted, dramatic loss of mdDA neurons and striatal innervation defects were observed, partially reminiscent of defects observed in Pitx3-/- mice. We then continue to reveal developmental crosstalk between En1 and Pitx3 through genome-wide expression analysis. During development, both En1 and Pitx3 are required to induce expression of mdDA genes in the rostrolateral subset destined to form the SNc. By contrast, Pitx3 and En1 reciprocally regulate a separate gene cluster, which includes Cck, demarcating a caudal mdDA subset in wild-type embryos. Whereas En1 is crucial for induction of this caudal phenotype, Pitx3 antagonizes it rostrolaterally. The combinatorial action of En1 and Pitx3 is potentially realized through at least three levels of molecular interaction: (1) influencing each other’s expression level, (2) releasing histone deacetylase-mediated repression of Nurr1 target genes and (3) modulating En1 activity through Pitx3-driven activation of En1 modulatory proteins. These findings show how two crucial mediators of mdDA neuronal development, En1 and Pitx3, interact in dopaminergic subset specification, the importance of which is exemplified by the specific vulnerability of the SNc found in PD.

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“…Approximately 200 kidneys were dissected in PBS/PMSF from E15.5 embryos and processed for ChIP as described Vitobello et al, 2011). The primers used to detect conserved elements (E1, E2, E3) and a control region outside of the conserved regions (OUT) following standard PCR conditions on ABI 7900HT machine (Applied Biosystems) are listed in supplementary materials and methods.…”

Section: Chromatin Immunoprecipitationmentioning

confidence: 99%

Pbx1 dependent control of VMC differentiation kinetics underlies gross renal vascular patterning

et al. 2015

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The architecture of an organ's vascular bed subserves its physiological function and metabolic demands. However, the mechanisms underlying gross vascular patterning remain elusive. Using intravital dye labeling and 3D imaging, we discovered that systems-level vascular patterning in the kidney is dependent on the kinetics of vascular mural cell (VMC) differentiation. Conditional ablation of the TALE transcription factor Pbx1 in renal VMC progenitors in the mouse led to the premature upregulation of PDGFRβ, a master initiator of VMC-blood vessel association. This precocious VMC differentiation resulted in nonproductive angiogenesis, abnormal renal arterial tree patterning and neonatal death consistent with kidney dysfunction. Notably, we establish that Pbx1 directly represses Pdgfrb, and demonstrate that decreased Pdgfrb dosage in conditional Pbx1 mutants substantially rescues vascular patterning defects and neonatal survival. These findings identify, for the first time, an in vivo transcriptional regulator of PDGFRβ, and reveal a previously unappreciated role for VMCs in systems-level vascular patterning.

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Hox and Pbx Factors Control Retinoic Acid Synthesis during Hindbrain Segmentation

Cited by 86 publications

References 64 publications

Retinoic acid signalling during development

Retinoic acid signalling during development

Specification of dopaminergic subsets involves interplay of En1 and Pitx3

Pbx1 dependent control of VMC differentiation kinetics underlies gross renal vascular patterning

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