A MODEL OF NEOCORTICAL AREA PATTERNING IN THE LISSENCEPHALIC MOUSE MAY HOLD FOR LARGER GYRENCEPHALIC BRAINS

Abstract

In the mouse, two telencephalic signaling centers orchestrate embryonic patterning of the cerebral cortex. From the rostral patterning center in the telencephalon (RPC), the Fibroblast Growth Factor, FGF8, disperses as a morphogen to establish the rostral to caudal (R/C) axis of the neocortical area map. FGF8 coordinates with Wnt3a from the cortical hem to regulate graded expression of transcription factors that position neocortical areas, and control hippocampal development. Whether similar signaling centers pattern the much larger cortices of carnivore and primate species, however, is unclear. The limited dispersion range of FGF8 and Wnt3a is inconsistent with patterning larger cortical primordia. Yet the implication that different mechanisms organize cortex in different mammals flies in the face of the tenet that developmental patterning mechanisms are conserved across vertebrate species. In the present study, both signaling centers were identified in the ferret telencephalon, as were expression gradients of the patterning transcription factor genes regulated by FGF8 and Wnt3a. Notably, at the stage corresponding to the peak period of FGF8 signaling in the mouse neocortical primordium (NP), the NP was the same size in ferret and mouse, which would allow morphogen patterning of the ferret NP. Subsequently the size of ferret neocortex shot past that of the mouse. Images from online databases further suggest that NP growth in humans, too, is slowed in early cortical development. We propose that if early growth in larger brains is held back, mechanisms that pattern the neocortical area map in the mouse could be conserved across mammalian species.

Graphical Abstract

Embryonic morphogens, including FGF8, initiate functional division of mouse cerebral cortex. In ferrets, the cortex is far larger, but at the critical developmental stage, the cortical primordia of the mouse and ferret are the same size, suggesting that morphogens with a limited range can pattern ferret and even human cortex.