Sfrp1 Modulates Cell-signaling Events Underlying Telencephalic Patterning, Growth and Differentiation.

The mammalian dorsal telencephalic neuroepithelium develops-from medial to lateral-into the choroid plaque, cortical hem, hippocampal primordium and isocortex under the influence of Bmp, Wnt and Notch signaling. Correct telencephalic development requires a tight coordination of the extent/duration of these signals, but the identification of possible molecular coordinators is still limited. Here, we postulated that Secreted Frizzled Related Protein 1 (Sfrp1), a multifunctional regulator of Bmp, Wnt and Notch signaling strongly expressed during early telencephalic development, may represent 1 of such molecules. We report that in E10.5-E12.5 Sfrp1-/- embryos, the hem and hippocampal domains are reduced in size whereas the prospective neocortex is medially extended. These changes are associated with a significant reduction of the medio-lateral telencephalic expression of Axin2, a read-out of Wnt/βcatenin signaling activation. Furthermore, in the absence of Sfrp1, Notch signaling is increased, cortical progenitor cell cycle is shorter, with expanded progenitor pools and enhanced generation of early-born neurons. Hence, in postnatal Sfrp1-/- animals the anterior hippocampus is reduced and the neocortex is shorter in the antero-posterior and medio-lateral axis but is thicker. We propose that, by controlling Wnt and Notch signaling in opposite directions, Sfrp1 promotes hippocampal patterning and balances medio-lateral and antero-posterior cortex expansion.

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