Alain Prochiantz

Can transcription factors function as cell–cell signalling molecules?

Recent data support the view that transcription factors — in particular, homeoproteins — can be transferred from cell to cell and have direct non-cell-autonomous (and therefore paracrine) activities. This intercellular transfer, based on atypical internalization and secretion, has important biotechnological consequences. But the real excitement stems from the physiological and developmental implications of this mode of signal transduction.

A Common Exocytotic Mechanism Mediates Axonal and Dendritic Outgrowth

Outgrowth of the dendrites and the axon is the basis of the establishment of the neuronal shape, and it requires addition of new membrane to both growing processes. It is not yet clear whether one or two exocytotic pathways are responsible for the respective outgrowth of axons and dendrites. We have previously shown that tetanus neurotoxin-insensitive vesicle-associated membrane protein (TI-VAMP) defines a novel network of tubulovesicular structures present both at the leading edge of elongating dendrites and axons of immature hippocampal neurons developing in primary culture and that TI-VAMP is an essential protein for neurite outgrowth in PC12 cells. Here we show that the expression of the N-terminal domain of TI-VAMP inhibits the outgrowth of both dendrites and axons in neurons in primary culture. This effect is more prominent at the earliest stages of the development of neurons in vitro. Expression of the N-terminal domain deleted form of TI-VAMP has the opposite effect. This constitutively active form of TI-VAMP localizes as the endogenous protein, particularly concentrating at the leading edge of growing axons. Our results suggest that a common exocytotic mechanism that relies on TI-VAMP mediates both axonal and dendritic outgrowth in developing neurons.

TRANSCRIPTION FACTOR HOXA-5 IS TAKEN UP BY CELLS IN CULTURE AND CONVEYED TO THEIR NUCLEI

Homeoproteins are transcription factors known to be involved in the early patterning of the nervous system and in lineage decisions. While studying a possible role for homeoproteins at later stages of neuronal differentiation, we observed that the Antennapedia homeodomain is internalized by neurons, translocated to their nuclei, and enhances neurite outgrowth. Studies with mutant homeodomains showed that neurite elongation by post-mitotic vertebrate neurons is regulated by homeoproteins. An intriguing possibility suggested by these results, is that full length homeoproteins might be able to translocate through neuronal membranes. We now report that the entire Hoxa-5 homeoprotein is taken up by fibroblasts and neurons in culture and conveyed to their nuclei. Internalization occurs at 4 and 37 degrees C, and at concentrations as low as 10 pM compatible with a physiological mechanism.

Neuronal polarity: Giving neurons heads and tails

The concept of neuronal polarity originates in the schematic view that information released in the form of a chemical signal by axon terminals is received by the dendrites of another neuron and forwarded to the cell body, where it is integrated before being conveyed to the axon. Although this idea of a uniform directionality of the flow of information is naive, it does suggest that axons and den-drites are different, and thereby has stimulated several studies aimed at understanding the molecular and structural bases of this difference. While understanding how neuronal polarity is created and maintained is of interest primarily to developmental and cell biologists, it is also important for those interested in the molecular and cellular bases of animal behavior, since the general geometry of the neurons is an important parameter for the functioning of neuronal circuits. Moreover , the shape of axonat and dendritic teminals is not fixed forever following synaptogenesis, but rather remains highly plastic; the morphological changes observed throughout adulthood are directly correlated with neuronal activity. It is thus possible that identifying factors that can modify axonal or dendritic elongation or morphology during neuronal development might yield some clues for a better understanding of higher brain functions such as learning and memory. Axons and Dendrites Only the major differences between axons and dendrites are discussed in this section, and possible exceptions related to a given neuronal type will not be described. At the optical level, axons are long and thin, their diameters do not change with distance from the cell body, and they branch at right angles. Intensive branching generally occurs distally, as they invade a target territory. In contrast, dendrites are shorter (again there are exceptions) and quite thick at their origin, but they taper rapidly as they produce several branches (for a review, see Craig and Banker, 1994). Seen at the ultrastructural level, dendrites contain almost all of the organelles that can be found in the cell body cytoplasm. In particular, the presence of free and membrane-bound ribosomes suggests that dendrites are the site of intense protein synthesis. This idea is corroborated by experiments demonstrating the presence of mRNAs in the dendrites. Interestingly, only mRNAs coding for dendrite-specific proteins can be found, suggesting the existence of mRNA sequences specific for dendrite addressing (Craig and Banker, 1994). Beyond the axon hill-ock, there are few exceptions to the virtual absence of ribosomes and mRNAs in the …

P2-067: Protein targets involved in the mechanisms of cell death induced by an amyloid precursor protein cytoplasmic subdomain

GFAP and light expressed in microglia cells, while there were large granular staining for synaptophysin around both GFAP containing cells and activated microglia. These results indicate that distinct changes occur in both types of synaptic components associated with A deposit and thus the punctuate increase in synaptophysin and chromogranin A immunoreactivities associated with A deposit and with reactive microglia might reflecting neuronal dysfunction.