Fez family transcription factors: controlling neurogenesis and cell fate in the developing mammalian nervous system

Abstract

Fezf1 and Fezf2 are highly conserved transcription factors that were first identified by their specific expression in the anterior neuroepithelium of Xenopus and zebrafish embryos. These proteins share an N-terminal domain with homology to the canonical engrailed repressor motif and a C-terminal DNA binding domain containing six C2H2 zinc-finger repeats. Over a decade of study indicates that the Fez proteins play critical roles during nervous system development in species as diverse as fruit flies and mice. Herein we discuss recent progress in understanding the functions of Fezf1 and Fezf2 in neurogenesis and cell fate specification during mammalian nervous system development. Going forward we believe that efforts should focus on understanding how expression of these factors is precisely regulated, and on identifying target DNA sequences and interacting partners. Such knowledge may reveal the mechanisms by which Fezf1 and Fezf2 accomplish both independent and redundant functions across diverse tissue and cell types.

Keywords: Fezf1; Fezf2; cell fate; cerebral cortex; gene expression; neurogenesis; olfactory system.

Figure 1

The Fez family of transcription factors. A: Schematic of FEZF1 and FEZF2 proteins highlighting the strong evolutionary conservation of the Engrailed homology 1 (Eh1) and zinc-finger DNA binding domains. Conservation is reported as percent homology to Homo sapiens FEZF1. B: Phylogenetic tree of FEZ family transcription factors. A single duplication event appears to have created the two FEZ proteins from a common ancestor.

Figure 2

Fezf1 and Fezf2 expression during embryogenesis. A: At E10.5 Fezf1 is expressed in progenitor cells in the forebrain and olfactory pit. Fezf2 is also expressed in forebrain progenitor cells; however within the olfactory pit its expression is restricted to the future VNO. B: By late gestation (E15.5), Fezf1 expression remains within the olfactory epithelium, but is absent from the cerebral cortex, and is decreasing within the VNO. In addition, it is expressed within the developing amygdala and hypothalamus. In contrast, Fezf2 expression remains high within the developing VNO and cerebral cortex. Within the cerebral cortex, Fezf2 is expressed at high levels in deep-layer postmitotic neurons and at a lower level in progenitor cells. Fezf2 is also expressed in the hypothalamus. C: At birth, expression of Fezf1 and Fezf2 largely mimics that at E15.5. Within the VNO, expression of Fezf2 has become restricted to the sustantacular cell layer. Within the cerebral cortex it maintains a high expression level in L5 SCPNs and lower levels in L6 CThPNs. Green represents Fezf1 expression, while purple represents Fezf2 expression.

Figure 3

Functions of Fezf1 and Fezf2 during olfactory system development. A: In Fezf1^−/− mice, olfactory sensory neurons express decreased levels of MOE enriched genes and instead up-regulate VNO enriched genes. This is accompanied by the failure of OSN axons to cross the cribriform plate and innervate the olfactory bulb. B: The VNO initially segregates away from the developing olfactory pit in Fezf2^−/− mice; however, it is substantially smaller. Because of decreased proliferation and increased apoptosis, VNO sensory neurons and sustantacular cells are completely absent at birth.

Figure 4

Fezf1 and Fezf2 functions during forebrain neurogenesis. A: Loss of both Fezf1 and Fezf2 during early forebrain neurogenesis results in an increase in HES5 expression. This leads to decreased neurogenesis and intermediate progenitor generation and decreases in the number of deep-layer projection neurons at birth. B: Fezf2 is expressed in multipotent RGCs that sequentially generate all major cortical projection neuron subtypes and glia.

Figure 5

Control of neocortical projection neuron fate by Fezf2. A: In wildtype mice Fezf2 is expressed at high levels in L5 SCPNs that send axons to the midbrain, hindbrain and spinal cord and at lower levels in CThPNs that project to the thalamus. Fezf2^−/− mice fail to generate subcerebral projections, and instead increased projections to the thalamus are observed. In the absence of Fezf2, L5 neurons extend axons across the corpus callosum, similar to CPNs. B: Gene expression changes after loss of Fezf2 suggest that it represses alternate CPN and CThPN fates. C: A model of the genetic interactions involving Fezf2 during generation of distinct cortical projection neuron subtypes.