RESUMEN
While TGF-ß signaling is essential for microglial function, the cellular source of TGF-ß1 ligand and its spatial regulation remains unclear in the adult CNS. Our data supports that microglia but not astrocytes or neurons are the primary producers of TGF-ß1 ligands needed for microglial homeostasis. Microglia-Tgfb1 KO leads to the activation of microglia featuring a dyshomeostatic transcriptome that resembles disease-associated, injury-associated, and aged microglia, suggesting microglial self-produced TGF-ß1 ligands are important in the adult CNS. Astrocytes in MG-Tgfb1 inducible (i)KO mice show a transcriptome profile that is closely aligned with an LPS-associated astrocyte profile. Additionally, using sparse mosaic single-cell microglia KO of TGF-ß1 ligand we established an autocrine mechanism for signaling. Here we show that MG-Tgfb1 iKO mice present cognitive deficits, supporting that precise spatial regulation of TGF-ß1 ligand derived from microglia is required for the maintenance of brain homeostasis and normal cognitive function in the adult brain.
Asunto(s)
Comunicación Autocrina , Cognición , Homeostasis , Ratones Noqueados , Microglía , Factor de Crecimiento Transformador beta1 , Animales , Microglía/metabolismo , Factor de Crecimiento Transformador beta1/metabolismo , Ratones , Cognición/fisiología , Astrocitos/metabolismo , Transducción de Señal , Encéfalo/metabolismo , Masculino , Transcriptoma , Ratones Endogámicos C57BL , Neuronas/metabolismoRESUMEN
While TGF-ß signaling is essential for microglial function, the cellular source of TGF-ß ligand and its spatial regulation remains unclear in the adult CNS. Our data support that microglia, not astrocytes or neurons, are the primary producers of TGF-ß1 ligands needed for microglial homeostasis. Microglia (MG)-Tgfb1 inducible knockout (iKO) leads to the activation of microglia featuring a dyshomeostatic transcriptomic profile that resembles disease-associated microglia (DAMs), injury-associated microglia, and aged microglia, suggesting that microglial self-produced TGF-ß1 ligands are important in the adult CNS. Interestingly, astrocytes in MG-Tgfb1 iKO mice show a transcriptome profile that closely aligns with A1-like astrocytes. Additionally, using sparse mosaic single-cell microglia iKO of TGF-ß1 ligand, we established an autocrine mechanism for TGF-ß signaling. Importantly MG-Tgfb1 iKO mice show cognitive deficits, supporting that precise spatial regulation of TGF-ß1 ligand derived from microglia is critical for the maintenance of brain homeostasis and normal cognitive function in the adult brain.
RESUMEN
A model was previously proposed that DA neurons provide SHH ligand to striatal interneurons, which in turn support the survival of DA neurons through the release of trophic factors such as Glial cell-derived neurotrophic factor (GDNF). However, some key clinical observations do not support this proposed model, and a recent independent study shows that striatal cholinergic neuron survival does not rely on intact DA neuron projections. To resolve this discrepancy, we generated several independent mouse lines to examine the exact role of DA neuron-derived Shh signaling in the maintenance of the basal ganglia circuit and to identify the Shh-producing cells in the adult brain. Our data suggest that the deletion of Shh in DA neurons does not affect DA neuron survival or locomotive function in cKO mice during aging, nor does it affect the long-term survival of cholinergic or FS PV + interneurons in the striatum (STR).