The role of FGF signaling in early embryonic forebrain development
The telencephalon, or forebrain, develops from the most anterior part of the embryonic neuroepithelium. During embryonic brain development, the dorsal-ventral specification of telencephalic cells is controlled by intricate interactions between three distinct signaling centers that are located along the medial part of the developing telencephalon. The dorsal center secretes bone morphogenic proteins (BMPs) and Wingless-Int proteins (Wnts), the rostral center secretes fibroblast growth factors (FGFs), and the ventral center secretes sonic hedgehog (SHH).;Deletion of Shh leads to the loss of ventral cell types. Deleting Gli3, which promotes BMP and Wnt signaling dorsally, leads to the loss of the dorsal forebrain and expansion of ventral cell identities dorsally. Remarkably, deleting both Shh and Gli3 essentially restores normal dorsal-ventral patterning of the telencephalon. Three fibroblast growth factor receptors (FGFRs) are expressed in the developing telencephalon: FGFR1, FGFR2, and FGFR3. We utilized the Cre/loxP system to specifically remove all possible combinations of FGFR pairs during early forebrain development. We showed that a gradual decrease in FGF signaling leads to progressively more severe phenotypes in the ventral telencephalon.;Multiple in vitro studies suggested that a small family of docking proteins named fibroblast growth factor receptor substrate (FRS) is responsible for the intracellular transduction of FGF signaling. There are two members of the FRS family: FRS2 and FRS3. FRS2 was shown in in vitro studies to be the major transducer of downstream FGF signaling. However, there is lack of evidence showing the in vivo role of FRS family of proteins in the transmission of FGF signaling. We decided to check the in vivo role of FRS family of proteins during telencephalic development. We utilized a loss of function approach to evaluate the roles of FRS2 and FRS3 proteins in the transmission of FGF signaling in early telencephalic development. Our results showed that the loss of FRS proteins leads to the loss of differentiated medial ganglionic eminence (MGE) cells in the developing telencephalon. Therefore, our work demonstrates that the FRS family of proteins is not required for the bulk of FGF signaling transmission, contradicting the in-vitro findings.
Source: Dissertation Abstracts International, Volume: 75-03(E), Section: B.;Advisors: Nicholas Baker; Jean Hebert.