TY - JOUR
T1 - Differential erbB signaling in astrocytes from the cerebral cortex and the hypothalamus of the human brain
AU - Sharif, Ariane
AU - Duhem-Tonnelle, Véronique
AU - Allet, Cécile
AU - Baroncini, Marc
AU - Loyens, Anne
AU - Kerr-Conte, Julie
AU - Collier, Francis
AU - Blond, Serge
AU - Ojeda, Sergio R.
AU - Junier, Marie Pierre
AU - Prevot, Vincent
PY - 2009
Y1 - 2009
N2 - Studies in rodents have shown that astroglial erbB tyrosine kinase receptors are key regulatory elements in neuronglia communication. Although both astrocytes and deregulation of erbB functions have been implicated in the pathogenesis of many common human brain disorders, erbB signaling in native human brain astrocytes has never been explored. Taking advantage of our ability to perform primary cultures from the cortex and the hypothalamus of human fetuses, we conducted a thorough analysis of erbB signaling in human astrocytes. We showed that human cortical astrocytes express erbB1, erbB2, and erbB3, whereas human hypothalamic astrocytes express erbB1, erbB2, and erbB4 receptors. Ligand-dependent activation of different erbB receptor heterodimeric complexes in these two populations of astrocytes translated into different morphological and proliferative responses. Although morphological plasticity was more pronounced in hypothalamic astrocytes than in cortical astrocytes, the former showed a lower mitogenic potential. Decreasing erbB4 expression via siRNA-mediated gene knockdown revealed that erbB4 constitutively restrains basal proliferative activity in hypothalamic astrocytes. We further show that treatment of human astrocytes with a protein kinase C activator results in rapid tyrosine phosphorylation of erbB receptors that involves cleavage of endogenous membrane bound erbB ligands by metalloproteinases. Together, these results indicate that erbB signaling in primary human brain astrocytes is functional, region-specific, and can be activated in a paracrine and/or autocrine manner. In addition, by revealing that some aspects of astroglial erbB signaling are different between human and rodents, our results provide a molecular framework to explore the potential involvement of astroglial erbB signaling deregulation in human brain disorders.
AB - Studies in rodents have shown that astroglial erbB tyrosine kinase receptors are key regulatory elements in neuronglia communication. Although both astrocytes and deregulation of erbB functions have been implicated in the pathogenesis of many common human brain disorders, erbB signaling in native human brain astrocytes has never been explored. Taking advantage of our ability to perform primary cultures from the cortex and the hypothalamus of human fetuses, we conducted a thorough analysis of erbB signaling in human astrocytes. We showed that human cortical astrocytes express erbB1, erbB2, and erbB3, whereas human hypothalamic astrocytes express erbB1, erbB2, and erbB4 receptors. Ligand-dependent activation of different erbB receptor heterodimeric complexes in these two populations of astrocytes translated into different morphological and proliferative responses. Although morphological plasticity was more pronounced in hypothalamic astrocytes than in cortical astrocytes, the former showed a lower mitogenic potential. Decreasing erbB4 expression via siRNA-mediated gene knockdown revealed that erbB4 constitutively restrains basal proliferative activity in hypothalamic astrocytes. We further show that treatment of human astrocytes with a protein kinase C activator results in rapid tyrosine phosphorylation of erbB receptors that involves cleavage of endogenous membrane bound erbB ligands by metalloproteinases. Together, these results indicate that erbB signaling in primary human brain astrocytes is functional, region-specific, and can be activated in a paracrine and/or autocrine manner. In addition, by revealing that some aspects of astroglial erbB signaling are different between human and rodents, our results provide a molecular framework to explore the potential involvement of astroglial erbB signaling deregulation in human brain disorders.
KW - Cerebral cortex
KW - Glial cells
KW - Growth factor
KW - Hypothalamus
KW - Neuron-glial interactions
UR - http://www.scopus.com/inward/record.url?scp=66249119372&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=66249119372&partnerID=8YFLogxK
U2 - 10.1002/glia.20762
DO - 10.1002/glia.20762
M3 - Article
C2 - 18803307
AN - SCOPUS:66249119372
SN - 0894-1491
VL - 57
SP - 362
EP - 379
JO - GLIA
JF - GLIA
IS - 4
ER -