Zinc finger gene fez‐like functions in the formation of subplate neurons and thalamocortical axons

Abstract

fez-like (fezl) is a forebrain-expressed zinc finger gene required for the formation of the hypothalamic dopaminergic and serotonergic (monoaminergic) neurons in zebrafish. To reveal its function in mammals, we analyzed the expression of the mouse orthologue of fezl and generated fezl-deficient mice by homologous recombination. Mouse fezl was expressed specifically in the forebrain from embryonic day 8.5. At mid-gestation, fezl expression was detected in subdomains of the forebrain, including the dorsal telencephalon and ventral diencephalon. Unlike the zebrafish fezl mutant too few, the fezl-deficient mice displayed normal development of hypothalamic monoaminergic neurons, but showed abnormal "hyperactive" behavior. In fezl -/-mice, the thalamocortical axons (TCA) were reduced in number and aberrantly projected to the cortex. These mutants had a reduced number of subplate neurons, which are involved in guiding the TCA from the dorsal thalamus, although the subplate neurons were born normally. These results suggest that fezl is required for differentiation or survival of the subplate neurons, and reduction of the subplate neurons in fezl-deficient mice leads to abnormal development of the TCA, providing a possible link between the transcriptional regulation of forebrain development and hyperactive behavior. Developmental Dynamics 230: 546 -556, 2004.

Fezl regulates the differentiation and axon targeting of layer 5 subcortical projection neurons in cerebral cortex

“…Consistent with a previous study of Fezl mutants (19), heterozygous Fezl ϩ/Ϫ mice produced homozygous Fezl Ϫ/Ϫ progeny at a Mendelian ratio, and locomotor activity tests revealed that Fezl Ϫ/Ϫ mice were twice as active as littermate controls (control, 161.4 Ϯ 64.3 counts per day; Fezl Ϫ/Ϫ , 335.5 Ϯ 126.7 counts per day, P ϭ 0.0039). Mutant brains appeared grossly normal, with clear evidence of cortical lamination (Fig.…”

“…6 C-F). Although defects in subplate neurons and thalamocortical projections have been reported in Fezl mutants (19), subplate neurons were present in the mutants generated here, as revealed by cresyl violet staining ( Fig. 6 E and F) and expression of Tbr1 (Fig.…”

“…The earliest expression of Ctip2 is observed in postmitotic neurons in lateral cortex at E14, with expression spreading medially over time (24). Fezl, in contrast, is first detected in the forebrain ventricular zone at E8.5, and expression remains strong during the production and differentiation of deep-layer neurons (19). This timing suggests that Fezl acts upstream of Ctip2 to control the differentiation of deeplayer neurons.…”

The determination of projection neuron identity in the developing cerebral cortex

“…However, others do appear to play important roles in fate determination. For example, the zinc-finger transcription factor Fezf2 is expressed in telencephalic progenitor cells starting at E8.5, and its expression is retained by deep layer neurons during corticogenesis [12,[30][31][32][33]. Layer 5 and 6 neurons subsequently acquire the expression of a second zinc finger transcription factor, Ctip2, during postmitotic differentiation [12,32,34].…”

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

“…These neurons fail to extend axons into the spinal cord in Ctip2 Ϫ/Ϫ mice (22). Fezf2 expression is detected in early forebrain progenitors and in their postmitotic progeny in cortical layers 5 and 6 (19)(20)(21)23). In Fezf2 Ϫ/Ϫ mice, deep-layer neurons are generated and migrate into appropriate positions but fail to express Ctip2 and other markers of layers 5 and 6 (19,20).…”