The Fezf2–Ctip2 genetic pathway regulates the fate choice of subcortical projection neurons in the developing cerebral cortex

Abstract

Pyramidal neurons in the deep layers of the cerebral cortex can be classified into two major classes: callosal projection neurons and long-range subcortical neurons. We and others have shown that a gene expressed specifically by subcortical projection neurons, Fezf2, is required for the formation of axonal projections to the spinal cord, tectum, and pons. Here, we report that Fezf2 regulates a decision between subcortical vs. callosal projection neuron fates. callosal ͉ cell fate ͉ zinc finger transcription factor ͉ corticospinal tract ͉ axon guidance

A network of genetic repression and derepression specifies projection fates in the developing neocortex

“…2 I and J), consistent with the interpretation (Fig. S1B) that at least some neurons that normally express Fezf2 acquire a callosal identity in the absence of Fezf2, possibly owing to acquisition of Satb2 expression (8).…”

“…2 A and E) and thalamus (Fig. S4I), whereas labeled axons are absent from the CC, as previously described (8,11). At P0, PLAP + axons descend subcerebrally and branch toward the thalamus (Fig.…”

“…1O). Without Fezf2, SCPNs up-regulate Satb2, switch fate, and extend axons across the CC (8), suggesting that Fezf2 represses Satb2 and the acquisition of a callosal identity. Conversely, without Satb2, callosal neurons up-regulate Ctip2 (but not Fezf2) and project subcortically (9,10).…”

Area-specific temporal control of corticospinal motor neuron differentiation by COUP-TFI

“…Several studies have demonstrated that the fate specification and differentiation of CSMN are under the control of a combinatorial set of transcription factors that can either induce or inhibit CSMN-specific genes during corticogenesis (8,9,21,28,29). In the present study, we provide evidence that COUP-TFI is an upstream negative regulator of a CSMN differentiation program in corticofugal neurons, through repression of a genetic program of CSMN differentiation.…”

“…It is likely that abnormal expression of corticothalamic neuron genes during CSMN differentiation, and dysregulation of CSMN "control genes" centrally contribute to improper differentiation of these neurons. In support of this latter hypothesis, ectopic expression of Fezf2 and CTIP2 leads to altered axonal trajectories (6,28), and dose-dependant effects of CTIP2 on CSMN differentiation have been reported (4,8). indicating that precise levels of CSMN-specific genes are a fundamental requisite for correct differentiation of corticofugal neurons.…”