Regulation of self-renewing neural progenitors by FGF-ERK signaling controls formation of the inferior colliculus

Abstract

During embryogenesis, the tectum (dorsal midbrain) displays gradients in both gene expression and cytogenesis along the anteroposterior axis, and eventually produces the superior colliculus anteriorly and inferior colliculus posteriorly. Although it is known that different strengths and durations of FGF signaling control the developmental gradient and cell fate decision in the developing tectum, the underlying mechanism and signaling cascade downstream of FGF remains unclear. Here, we showed that deleting Shp2, which links FGF with the ERK pathway, prevented inferior colliculus formation by depleting a previously uncharacterized stem cell zone, designated as tectal stem zone, in the posterior part of the developing tectum. The loss of the tectal stem zone was associated with decreased cell-cycle reentry, accelerated neurogenesis, and shortened S phase of the cell cycle. Expressing a constitutively active ERK activator, Mek1DD, restored the tectal stem zone and thereby the inferior colliculus without Shp2. We showed that Mek1DD expression prevented cell death in the mesencephalon without Fgf8, allowing examination of tectal development without the so-called isthmic organizer for the first time to the best of our knowledge. Interestingly, although Mek1DD expression induced wild-spread expression of FGF targets that are normally expressed in gradients in the tectum, it failed to rescue the tectal stem zone and the inferior colliculus without Fgf8, indicating that Fgf8 and Mek1DD initiate qualitatively and/or quantitatively distinctive signaling. Therefore, the formation of the inferior colliculus relies on the provision of new cells from the tectal stem zone. Furthermore, distinctive ERK signaling mediates Fgf8 in the control of cell survival, tissue polarity, and cytogenetic gradient during the development of the tectum.