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ER-mitochondria tethering by PDZD8 regulates Ca2+ dynamics in mammalian neurons
Interfaces between organelles are emerging as critical platforms for many biological responses in eukaryotic cells. In yeast, the ERMES complex is an endoplasmic reticulum (ER)-mitochondria tether composed of four proteins, three of which contain a SMP (synaptotagmin-like mitochondrial-lipid binding protein) domain. No functional ortholog for any ERMES protein has been identified in metazoans. Here, we identified PDZD8 as an ER protein present at ER-mitochondria contacts. The SMP domain of PDZD8 is functionally orthologous to the SMP domain found in yeast Mmm1. PDZD8 was necessary for the formation of ER-mitochondria contacts in mammalian cells. In neurons, PDZD8 was required for calcium ion (Ca2+) uptake by mitochondria after synaptically induced Ca2+-release from ER and thereby regulated cytoplasmic Ca2+ dynamics. Thus, PDZD8 represents a critical ER-mitochondria tethering protein in metazoans. We suggest that ER-mitochondria coupling is involved in the regulation of dendritic Ca2+ dynamics in mammalian neurons
FGF signaling is strictly required to maintain early telencephalic precursor cell survival
The FGF family of extracellular signaling factors has been proposed to play
multiple roles in patterning the telencephalon, the precursor to the cerebrum.
In this study, unlike previous ones, we effectively abolish FGF signaling in
the anterior neural plate via deletion of three FGF receptor (FGFR) genes.
Triple FGFR mutant mice exhibit a complete loss of the telencephalon, except
the dorsal midline. Disruption of FGF signaling prior to and coincident with
telencephalic induction reveals that FGFs promote telencephalic character and
are strictly required to keep telencephalic cells alive. Moreover,
progressively more severe truncations of the telencephalon are observed in
FGFR single, double and triple mutants. Together with previous
gain-of-function studies showing induction of Foxg1 expression and
mirror-image duplications of the cortex by exogenous FGF8, our
loss-of-function results suggest that, rather than independently patterning
different areas, FGF ligands and receptors act in concert to mediate organizer
activity for the whole telencephalon