Tau-4R suppresses proliferation and promotes neuronal differentiation in the hippocampus of tau knockin/knockout mice.
Differential isoform expression and phosphorylation of protein tau are believed to regulate the assembly and stabilization of microtubuli in fetal and adult neurons. To define the functions of tau in the developing and adult brain, we generated transgenic mice expressing the human tau-4R/2N (htau-4R) isoform on a murine tau null background, by a knockout/knockin approach (tau-KOKI). The main findings in these mice were the significant increases in hippocampal volume and neuronal number, which were sustained throughout adult life and paralleled by improved cognitive functioning. The increase in hippocampal size was found to be due to increased neurogenesis and neuronal survival. Proliferation and neuronal differentiation were further analyzed in primary hippocampal cultures from tau-KOKI mice, before and after htau-4R expression onset. In absence of tau, proliferation increased and both neurite and axonal outgrowth were reduced. Htau-4R expression suppressed proliferation, promoted neuronal differentiation, and restored neurite and axonal outgrowth. We suggest that the tau-4R isoform essentially contributes to hippocampal development by controlling proliferation and differentiation of neuronal precursors.
Sennvik
Kristina
K
Experimental Genetics Group, Department Human Genetics, KULeuven-Campus Gasthuisberg ON1-06.602, B-3000 Leuven, Belgium.
Boekhoorn
Karin
K
Lasrado
Reena
R
Terwel
Dick
D
Verhaeghe
Steven
S
Korr
Hubert
H
Schmitz
Christoph
C
Tomiyama
Takami
T
Mori
Hiroshi
H
Krugers
Harm
H
Joels
Marian
M
Ramakers
Ger J A
GJ
Lucassen
Paul J
PJ
Van Leuven
Fred
F
D000818:Animals; D002454:Cell Differentiation; D002455:Cell Division; D003433:Crosses, Genetic; D004624:Embryo Transfer; D053595:Embryonic Stem Cells; D005106:Exploratory Behavior; D005822:Genetic Vectors; D006624:Hippocampus / Q000166:cytology* / Q000254:growth & development; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008845:Microinjections; D016501:Neurites / Q000648:ultrastructure; D009474:Neurons / Q000166:cytology*; D009929:Organ Size; D020033:Protein Isoforms / Q000235:genetics / Q000502:physiology; D021641:Recognition, Psychology; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000502:physiology; D013234:Stem Cells / Q000166:cytology; D014161:Transduction, Genetic; D016875:tau Proteins / Q000737:chemistry / Q000235:genetics / Q000502:physiology*
C054369:MAPT protein, human; D020033:Protein Isoforms; D011993:Recombinant Fusion Proteins; D016875:tau Proteins