Homeoprotein Signaling in Development, Health, and Disease: A Shaking of Dogmas Offers Challenges and Promises from Bench to Bed

Spatazza, Julien; Lullo, Elizabeth Di; Joliot, Alain; Dupont, Edmond; Moya, Kenneth L.; Prochiantz, Alain

doi:10.1124/pr.112.006577

Cited by 51 publications

(61 citation statements)

References 97 publications

(131 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Intercellular transfer has also been reported for other homeodomain transcription factors, such as engrailed-2 (En2) and orthodenticle homeobox 2 (Otx2) (Joliot et al, 1998; Sugiyama et al, 2008; Spatazza et al, 2013). However, little is known about the regulatory mechanisms underlying the trafficking of homeodomain transcription factors.…”

Section: Resultsmentioning

confidence: 87%

“…The differential affinities of Vax1 and Otx2 for HS and CS might be related to their different homeodomains. Among homeodomain proteins proven to exhibit transfer, Vax1 possesses an antennapedia class homeodomain homologous to that of Emx2 and En2, whereas Otx2 shares a paired class homeodomain similar to that of Pax6 (paired box 6) (Bürglin, 2011; Spatazza et al, 2013). One intriguing possibility that has not yet been explored is that these secreted homeodomain proteins share the property of preferential binding to HS and CS; however, it is at least as likely that intercellular transfer of homeodomain proteins are target-selective events.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Regulation of retinal axon growth by secreted Vax1 homeodomain protein

Kim

Min

Kang

et al. 2014

eLife

View full text Add to dashboard Cite

Retinal ganglion cell (RGC) axons of binocular animals cross the midline at the optic chiasm (OC) to grow toward their synaptic targets in the contralateral brain. Ventral anterior homeobox 1 (Vax1) plays an essential role in the development of the OC by regulating RGC axon growth in a non-cell autonomous manner. In this study, we identify an unexpected function of Vax1 that is secreted from ventral hypothalamic cells and diffuses to RGC axons, where it promotes axonal growth independent of its transcription factor activity. We demonstrate that Vax1 binds to extracellular sugar groups of the heparan sulfate proteoglycans (HSPGs) located in RGC axons. Both Vax1 binding to HSPGs and subsequent penetration into the axoplasm, where Vax1 activates local protein synthesis, are required for RGC axonal growth. Together, our findings demonstrate that Vax1 possesses a novel RGC axon growth factor activity that is critical for the development of the mammalian binocular visual system.DOI: http://dx.doi.org/10.7554/eLife.02671.001

show abstract

Section: Resultsmentioning

confidence: 87%

Section: Discussionmentioning

confidence: 99%

Regulation of retinal axon growth by secreted Vax1 homeodomain protein

Kim

Min

Kang

et al. 2014

eLife

View full text Add to dashboard Cite

show abstract

“…Over the past decade, this focus has greatly expanded with the discovery of the role that exosomes and their cargoes play in neuronal function [4][5][6], and the role that homeoproteins play in the adult brain [7][8][9][10]. We are now beginning to appreciate the possibility that the presynaptic neuron, via homeoproteins and exosomes, may change the internal computational machinery of the postsynaptic neuron by epigenetic-related mechanisms in remarkable ways.…”

Section: Introductionmentioning

confidence: 99%

The role of epigenetic-related codes in neurocomputation: dynamic hardware in the brain

Edelstein

Smythies

2014

Phil. Trans. R. Soc. B

View full text Add to dashboard Cite

This paper presents a review of recent work on the role that two epigeneticrelated systems may play in information processing mechanisms in the brain. The first consists of exosomes that transport epigenetic-related molecules between neurons. The second consists of homeoproteins like Otx2 that carry information from sense organs to primary sensory cortex. There is developing evidence that presynaptic neurons may be able to modulate the fine microanatomical structure in the postsynaptic neuron. This may be conducted by three mechanisms, of which the first is well established and the latter two are novel. (i) By the well-established activation of receptors that trigger a chain of signalling molecules (second messengers) that result in the upregulation and/or activation of a transcription factor. The two novel systems are the exosome system and homeoproteins. (ii) Exosomes are small vesicles that are released upon activation of the axon terminal, traverse the synaptic cleft, probably via astrocytes and are taken up by the postsynaptic neuron. They carry a load of signalling proteins and a variety of forms of RNA. These loads may then be transported widely throughout the postsynaptic neuron and engineer modulations in the fine structure of computational machinery by epigenetic-related processes. (iii) Otx2 is a transcription factor that, inter alia, controls the development and survival of PVþ GABAergic interneurons (PV cells) in the primary visual cortex. It is synthesized in the retina and is transported to the cortex by a presently unknown mechanism that probably includes direct cell-to-cell transfer, and may, or may not, include transfer by the dynein and exosome systems in addition. These three mechanisms explain a quantity of data from the field of de-and reafferentation plasticity. These data show that the modality of the presynaptic neuron controls to a large extent the modality of the postsynaptic neuron. However, the mechanism that effects this is currently unknown. The exosome and the homeoprotein hypotheses provide novel explanations to add to the well-established earlier mechanism described above.

show abstract

“…The third HP for which non-cell-autonomous functions have been identified is Otx2 [5]. The role of Otx2 transfer in the regulation of cerebral cortex plasticity will be developed in the main core of this review which from now on will be focused on postnatal and adult cell-autonomous and non-cell-autonomous activities of En1/2 and Otx2.…”

Section: Introductionmentioning

confidence: 99%

“…In addition to mediating DNA binding, the HD encompasses two short sequences allowing HP secretion and internalization to impart non-cell-autonomous functions [4]. Such functions have been studied in vivo for Engrailed-1 (En1) and Engrailed-2 (En2), collectively Engrailed or En1/2, for Otx2 and for Pax6 [5]. However, based on sequence alignments, it is likely that non-cell-autonomous functions are a property of many HPs, and a dozen HPs have been verified in vitro.…”

Section: Introductionmentioning

confidence: 99%

Postnatal signalling with homeoprotein transcription factors

Prochiantz

Fuchs

Nardo

2014

Phil. Trans. R. Soc. B

Self Cite

View full text Add to dashboard Cite

Homeoprotein (HP) transcription factors were originally identified for their embryonic cell-autonomous developmental functions. In this review, we discuss their postnatal and adult physiological functions based on the study of Otx2, Engrailed-1 and Engrailed-2 (collectively Engrailed). For Engrailed, we discuss its function in the cell-autonomous regulation of ventral midbrain dopaminergic neuron survival and physiology and in the non-cell-autonomous maintenance of axons. For Otx2, we describe how the protein is expressed in the choroid plexus and transported into cortical parvalbumin cells where it regulates plasticity in the visual cortex. These two examples illustrate how the understanding of HP postnatal and adult functions, including signalling functions, may lead to the identification of disease-associated genetic pathways and to the development of original therapeutic strategies.

show abstract

Homeoprotein Signaling in Development, Health, and Disease: A Shaking of Dogmas Offers Challenges and Promises from Bench to Bed

Cited by 51 publications

References 97 publications

Regulation of retinal axon growth by secreted Vax1 homeodomain protein

Regulation of retinal axon growth by secreted Vax1 homeodomain protein

The role of epigenetic-related codes in neurocomputation: dynamic hardware in the brain

Postnatal signalling with homeoprotein transcription factors

Contact Info

Product

Resources

About