Differential erbB signaling in astrocytes from the cerebral cortex and the hypothalamus of the human brain.
Studies in rodents have shown that astroglial erbB tyrosine kinase receptors are key regulatory elements in neuron-glia 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.
Sharif
Ariane
A
Inserm, Jean-Pierre Aubert Research Centre, U837, Development and Plasticity of the Postnatal Brain, Lille Cedex, France.
Duhem-Tonnelle
Véronique
V
Allet
Cécile
C
Baroncini
Marc
M
Loyens
Anne
A
Kerr-Conte
Julie
J
Collier
Francis
F
Blond
Serge
S
Ojeda
Sergio R
SR
Junier
Marie-Pierre
MP
Prevot
Vincent
V
D000704:Analysis of Variance; D001253:Astrocytes / Q000502:physiology*; D001973:Bromodeoxyuridine; D049109:Cell Proliferation; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology*; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism*; D027341:Excitatory Amino Acid Transporter 1 / Q000378:metabolism; D005333:Fetus; D005786:Gene Expression Regulation / Q000187:drug effects; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006801:Humans; D007031:Hypothalamus / Q000166:cytology*; D047468:Immunoprecipitation / Q000379:methods; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D020890:Neuregulin-1 / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000494:pharmacology; D066247:Receptor, ErbB-4; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D016211:Transforming Growth Factor alpha / Q000494:pharmacology; D014443:Tyrosine / Q000378:metabolism; D014746:Vimentin / Q000378:metabolism
D027341:Excitatory Amino Acid Transporter 1; D005904:Glial Fibrillary Acidic Protein; C489788:MAP2 protein, human; D008869:Microtubule-Associated Proteins; D009419:Nerve Tissue Proteins; D020890:Neuregulin-1; D034741:RNA, Small Interfering; C493394:SLC1A3 protein, human; D016211:Transforming Growth Factor alpha; D014746:Vimentin; C087230:heregulin beta1; D014443:Tyrosine; C587689:ERBB4 protein, human; D066246:ErbB Receptors; D066247:Receptor, ErbB-4; D001973:Bromodeoxyuridine