Emx2 homeodomain transcription factor interacts with eukaryotic translation initiation factor 4E (eIF4E) in the axons of olfactory sensory neurons

Nedelec, Stéphane; Foucher, Isabelle; Brunet, Isabelle; Bouillot, Colette; Prochiantz, Alain; Trembleau, Alain

doi:10.1073/pnas.0403824101

Cited by 84 publications

(65 citation statements)

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“…If one accepts the analogy between neurons and MDCK cells proposed by Dotti and Simons (25), this suggests that homeoproteins can be transported in the axons, released in the synaptic cleft, and recaptured at the post-synaptic level. In fact, Emx2 homeoprotein is transported into the axons of the olfactory receptor and accumulates in their terminals (26). Also in support of this idea is the recent demonstration that Otx2 homeoprotein can be transported from the retinal ganglion cells to interneurons of the visual cortex, with a relay in the dorsal thalamus (27).…”

Section: Discussionsupporting

confidence: 56%

Identification of a Signal Peptide for Unconventional Secretion

Dupont¹,

Prochiantz

Joliot³

2007

Journal of Biological Chemistry

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Homeoproteins are a class of transcription factors defined by the structure of their DNA-binding domain, the homeodomain. In addition to their nuclear cell-autonomous activities, homeoproteins transfer between cells, thanks to two separate steps of secretion and internalization, which both rely on unconventional mechanisms. Internalization is driven by the third helix of the homeodomain (Penetratin) through a non-vesicular and endocytosis-independent mechanism. In contrast, homeoprotein secretion involves vesicular compartments and requires the presence of a sequence of 11 amino acids (Sec sequence) spanning between the second and third helix of the homeodomain. In this study, we report that the SecPen polypeptide, which combines the two identified domains, Penetratin and Sec, bears all of the necessary information to go in and out of cells. We have analyzed key mechanisms and demonstrated that this peptide can efficiently cross a tight junction epithelium.Homeoproteins belong to a class of transcription factors with key developmental and adult functions. In addition to their nuclear cell-autonomous activities, they also have the ability to transfer between cells (1). The latter property likely serves specific paracrine functions. For example, the extracellular application of a gradient of Engrailed homeoprotein attracts or repulses the nasal or temporal growth cones of retinal ganglion cells, respectively, suggesting a non-cell autonomous function of Engrailed in axonal guidance (2). Homeoprotein intercellular transfer involves two separate steps of secretion and internalization. The homeodomain (the DNA-binding domain that defines homeoproteins) is necessary and sufficient for transfer (3), even though other parts of the protein are endowed with transfer regulatory functions (4). The two sequences required for secretion and internalization are highly conserved, and indeed, intercellular transfer is a shared property of several homeoproteins. Mutational analysis indicates that internalization and secretion rely on two distinct mechanisms (5). Internalization is driven by the third helix of the homeodomain (6). This 16-amino-acid-long peptide (thereafter Penetratin or Pen) 2 is internalized by live cells through a mechanism independent of endocytosis (7) and has been used extensively to address exogenous compounds into the cell cytoplasm and nucleus (see Ref. 8 for review). Homeoproteins are also secreted despite the absence of classical secretion signals. Using Engrailed-1 (En1) and Engrailed-2 (En2) as prototypic homeoproteins, it was shown that they are present in vivo in vesicles enriched in cholesterol and glycosphingolipids (9). The addressing of Engrailed proteins to this compartment and their secretion are abolished upon deletion of 11 amino acids spanning between the second and third helix of the homeodomain (5, 10), which was called the Sec sequence (see Fig. 3A). It thus suggests that this sequence participates in unconventional homeoprotein secretion (in the absence of secretion signal sequence).In t...

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Section: Discussionsupporting

confidence: 56%

Identification of a Signal Peptide for Unconventional Secretion

Dupont¹,

Prochiantz

Joliot³

2007

Journal of Biological Chemistry

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“…No evidence for the translation of odorant receptor or OMP mRNAs in sensory neuron axons has been reported thus far. Of particular interest, however, we have shown that the Emx2 homeodomain transcription factor is also transported into olfactory axons, where it interacts with the eIF4E translation initiation factor, a feature that suggests a regulated translation of mRNAs in these axons (Nédélec et al, 2004(Nédélec et al, , 2005. Furthermore, the observation of endogenous odorant receptors in the most distal segments of sensory axons within the olfactory bulb, but not in intermediate axon bundles connecting the epithelium to the bulb (Barnea et al, 2004;Strotmann et al, 2004), raises the question as to what molecular mechanisms control this intriguing axonal compartmentalization.…”

Section: Introductionmentioning

confidence: 99%

Evidence for Developmentally Regulated Local Translation of Odorant Receptor mRNAs in the Axons of Olfactory Sensory Neurons

Dubacq¹,

Jamet²,

Trembleau³

2009

J. Neurosci.

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Odorant receptor mRNAs are transported within axons of olfactory sensory neurons that project into the olfactory bulb. Odorant receptor proteins have been identified along the distal part of these axons, which raises the possibility of their local synthesis in axons. We took advantage of the anatomical separation between the olfactory mucosa (which contains the sensory neuron cell bodies) and the bulb (which contains sensory axons but no sensory neuron cell bodies) to address this issue using a quantitative biochemical approach. Combining a method that separates polysome-associated mRNAs from untranslated mRNAs with a reverse transcription-quantitative PCR approach, we demonstrate that significant amounts of odorant receptor mRNAs are associated with polysomes in the sensory axons of the adult mouse bulb. We thus provide the first evidence for local synthesis of odorant receptor proteins in these axons. Interestingly, the rate of odorant receptor mRNA translation in axons is significantly greater during periods when the proportion of immature axons is higher (i.e., at postnatal day 4 or on regeneration after chemical lesion in adults). In contrast, the olfactory marker protein mRNA, which is restricted to mature axons, is translated at a low and constant level. Overall, we demonstrate that translation levels of odorant receptor mRNAs in axons are developmentally regulated, and positively correlated to the stage of axonal growth into the bulb. Given the established function of odorant receptors in the axonal wiring of sensory projections, we propose that this regulated axonal translation may play a role in the development and maintenance of the glomerular array.

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“…This regulation, first observed in growth cones, probably engages the mTOR pathway as it is accompanied by the phosphorylation of eIF4E and 4E-BP1, two key regulators of protein translation 11 . Regulating translation may be a property of several homeoproteins since many of them, including Engrailed, bind eIF4E 12,13 .…”

Section: Introductionmentioning

confidence: 99%