RESUMO
The (pro)renin receptor [(P)RR], also known as ATP6AP2 [ATPase 6 accessory protein 2], is highly expressed in the brain. ATP6AP2 plays a role in early brain development, adult hippocampal neurogenesis and in cognitive functions. Lack of ATP6AP2 has deleterious effects, and mutations of ATP6AP2 in humans are associated with, e.g. X-linked intellectual disability. However, little is known about the effects of over-expression of ATP6AP2 in the adult brain. We hypothesized that mice over-expressing ATP6AP2 in the brain might exhibit altered neuroanatomical features and behavioural responses. To this end, we investigated heterozygous transgenic female mice and confirmed increased levels of ATP6AP2 in the brain. Our data show that over-expression of ATP6AP2 does not affect adult hippocampal neurogenesis, exercise-induced cell proliferation, or dendritic spine densities in the hippocampus. Only a reduced ventricular volume on the gross morphological level was found. However, ATP6AP2 over-expressing mice displayed altered exploratory behaviour with respect to the hole-board and novel object recognition tests. Moreover, primary adult hippocampal neural stem cells over-expressing ATP6AP2 exhibit a faster cell cycle progression and increased cell proliferation. Together, in contrast to the known deleterious effects of ATP6AP2 depletion, a moderate over-expression results in moderate behavioural changes and affects cell proliferation rate in vitro.
Assuntos
Comportamento Animal/fisiologia , Hipocampo/citologia , Hipocampo/fisiologia , Neurônios/citologia , ATPases Translocadoras de Prótons/metabolismo , Receptores de Superfície Celular/metabolismo , Animais , Ciclo Celular/genética , Proliferação de Células/genética , Ventrículos Cerebrais/anatomia & histologia , Adaptação à Escuridão/genética , Espinhas Dendríticas/metabolismo , Proteínas do Domínio Duplacortina , Epêndima/metabolismo , Comportamento Exploratório , Hipocampo/diagnóstico por imagem , Histonas/metabolismo , Aprendizagem em Labirinto/fisiologia , Camundongos , Camundongos Transgênicos , Proteínas Associadas aos Microtúbulos/metabolismo , Neurogênese/genética , Neuropeptídeos/metabolismo , ATPases Translocadoras de Prótons/genética , Receptores de Superfície Celular/genética , Reconhecimento Psicológico/fisiologia , Caracteres SexuaisRESUMO
The multifunctional cytokine transforming growth factor ß (TGFß) plays a dual role in prostate cancer (PCa), cell growth and tumorigenesis, reflected by its opposing properties of anti-oncogenic (e.g. growth inhibition and apoptosis) and pro-oncogenic effects (e.g. proliferation, cell motility and remodelling of the microenvironment). In the later stages of PCa, TGFß loses anti-proliferative and thereby tumor-suppressive functions and shifts to a tumorigenic phenotype, mainly initiated by cross-talk between TGFß signalling and other proliferation signal transduction pathways, such as mitogen-activated protein kinase (MAPK) and androgen receptor (AR) signalling. Although TGFß plays an important role in tumor progression little is known about the underlying effects of TGFß in the molecular pathology of PCa.
