The Physiology of Homeoprotein Transduction

Nardo, Ariel A. Di; Fuchs, Julia; Joshi, Rajiv L.; Moya, Kenneth L.; Prochiantz, Alain

doi:10.1152/physrev.00018.2017

Cited by 48 publications

(58 citation statements)

References 306 publications

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“…An aspect of HP functions that has recently attracted some attention is their ability to transfer between cells. This intercellular transport results in non-cell autonomous HP regulation of gene expression and potentially induces changes in the epigenetic status of the receiving cells (3). Although HP transduction in vivo and in vitro was only verified for about 15 HPs, the sequences responsible for HP internalization and secretion are highly conserved, strongly suggesting that transduction is a shared property of most of the 200-300 members of the HP family (4; 5).…”

Section: Introductionmentioning

confidence: 99%

Non-cell autonomous OTX2 transcription factor regulates anxiety-related behavior in the mouse

Vincent

Gilabert-Juan

Gibel-Russo

et al. 2019

Preprint

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The Otx2 homeoprotein transcription factor is expressed in the dopaminergic neurons of the ventral tegmental area, a mesencephalic nucleus involved in the control of complex behaviors through its projections to limbic structures, including the ventral hippocampus, amygdala, nucleus accumbens and prefrontal cortex. We find adult mice heterozygous for Otx2 show a hypoanxious phenotype in light-dark box and elevated plus maze paradigms. However, the number of dopaminergic neurons, the integrity of their axons, their projection patterns in target structures, and the amounts of dopamine and dopamine metabolites in targets structures were not modified in the Otx2 mutant. Because OTX2 is expressed by the choroid plexus, secreted into cerebrospinal fluid and transferred to parvalbumin interneurons of the cortex, hippocampus, and amygdala, we investigated if the hypoanxiety of Otx2 heterozygous mice could result from the decreased synthesis of Otx2 in the choroid plexus. Indeed, hypoanxious phenotype was reversed by the overexpression of Otx2 specifically in choroid plexus of adult Otx2 heterozygous mice, while hypoanxious phenotype could be induced in adult wild type mice by lowering OTX2 levels in the cerebrospinal fluid. Taken together, OTX2 synthesis by the choroid plexus followed by its secretion into the cerebrospinal fluid is an important regulator of the anxiety phenotype in the mouse. MATERIAL AND METHODS Ethics statementAll animal procedures, including housing, were carried out in accordance with the recommendations of the European Economic Community (86/609/EEC), the French National Committee (87/848) and French bylaws (AGRG1240332A / AGRG1238724A / AGRG1238767A / AGRG1238729A / AGRG1238753A). For surgical procedures, animals were anesthetized with Xylazine (Rompun 2%, 5 mg/kg) and Ketamine (Imalgene 500, 80 mg/kg). This research (project no. 00704.02) was approved by Ethics committee n° 59 of the French Ministry for Research and Higher Education. MiceThe Otx2-het mouse line was generated in the laboratory of Antonio Simeone (CEINGE, Naples), with the Otx2 coding sequence and introns replaced by GFP (20). Otx2 +/GFP males were crossed with B6D2F1 females to obtain Otx2-het mice. The single-chain antibody (scFv) OTX2 knock-in scFv-Otx2 mouse line was generated by the Institut Clinique de la Souris (Strasbourg, France) by inserting the scFv-Otx2 minigene construct in the Rosa26 locus (21). Mice were raised in a 12-hour light/dark cycle with 2 to 5 (males) or 6 (females) animals per cages. Temperature was controlled (21±3°C), and food and water provided ad libitum. AAV injectionsAdeno-associated viruses (AAV) were generated by Vector Biolabs: AAV5(CMV)-HAOtx2-2A-mCherry and AAV5(CMV)-mCherry. Stereotaxic injections were performed with a Hamilton syringe at a rate of 0.3 µl/min: 2 µl/lateral ventricle (bregma: x = ±1.28 mm, y = -0.58 mm, z = 2 mm). Mice were tested in the light-dark box and on the elevated-plus maze 3 and 4 weeks after injection, respectively. Cre-TAT protein injectionStereotaxic injection (bregma:...

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Section: Introductionmentioning

confidence: 99%

Non-cell autonomous OTX2 transcription factor regulates anxiety-related behavior in the mouse

Vincent

Gilabert-Juan

Gibel-Russo

et al. 2019

Preprint

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“…This is reminiscent of OTX2, another HP that specifically accumulates in parvalbumin interneurons of the cerebral cortex (3) following its specific binding to glycosaminoglycans (GAGs) via a GAG binding domain (RKQRRERTTFTRAQL) (21). Similar GAG-binding domains are present in many HPs (1,2), including EN1 and EN2 for which this putative GAG-binding sequence is KEDKRPRTAFTAEQL. The potential role of this domain in the specific targeting of EN1 and the presence of EN1binding sites at the αMN surface will be investigated in future studies.…”

Section: Discussionmentioning

confidence: 99%

“…Thus, large ChAT-expressing MNs are surrounded by En1-expressing cells. ENGRAILED1/2 is a transduction protein that directly signals between cells (2). Neutralizing extracellular EN1/2 in vivo modifies the maturation of the anterior cross vein in the fly wing disk and the navigation of retinal ganglion cell growth cones in frog and chick tectum (5,14).…”

Section: Neutralizing Extracellular En1 In the Adult Induces Motor Dementioning

confidence: 99%

“…Discovered on the basis of their developmental functions, homeoprotein (HP) transcription factors remain expressed in the adult where they participate in physiological homeostasis (1). HP functions involve cell autonomous and non-cell autonomous activities, a consequence of their ability to transfer between cells (2). Examples of in vivo non-cell autonomous activities include the regulation of cerebral cortex plasticity by OTX2 (3) the control of Cajal-Retzius cell migration by PAX6 (4) and the axon guidance activities of ENGRAILED and VAX-1 (5,6).…”

Section: Introductionmentioning

confidence: 99%

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Homeoprotein ENGRAILED-1 promotes motoneuron survival and motor functions

Abonce

Leboeuf

Moya

et al. 2019

Preprint

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Conflict of Interest Statement: AP and KLM are on several patents for HP therapeutic use and co-founders of BrainEver. SEVA and ML are BrainEver post-doctorant and doctorant, respectively.Funding sources: MemoLife Labex PhD fellowship to SEVA, Association Nationale de la Recherche et de la Technologie (Cifre/ANRT n° 2017/0488) to ML, BrainEver, HomeoSign ERC -2013-AdG n°339379. ABSTRACTMotoneuron degeneration leads to skeletal muscle denervation and impaired motor functions, yet the signals involved remain poorly understood. We find that extracellular ENGRAILED-1, a homeoprotein expressed in spinal cord V1 interneurons that synapse on α-motoneurons, has non-cell autonomous activity. Mice heterozygote for Engrailed-1 develop muscle weakness, abnormal spinal reflex and partial neuromuscular junction denervation. A single intrathecal injection of ENGRAILED-1 restores innervation, limb strength, extensor reflex and prevents lumbar α-motoneuron death for several months. The autophagy gene p62, which was found to network with Engrailed-1 and amyotrophic lateral sclerosis genes, is misregulated in Engrailed-1 heterozygote mice α-motoneurons and is rescued following ENGRAILED-1 injection. These results identify ENGRAILED-1 as an α-motoneuron trophic factor with long-lasting protective activity.

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“…Engrailed‐1 (EN1) and Engrailed‐2 are 2 homeoprotein cell‐transducing transcription factors with equivalent roles in the development and survival of midbrain dopaminergic neurons . Engrailed protects midbrain dopaminergic neurons against intoxication with 6‐hydroxydopamine, systemic 1‐methyl‐4‐phenyl‐1,2,3,6‐tetra‐hydropyridin (MPTP), or the A30P variant of α‐synuclein …”

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confidence: 99%