Abstract
Corticothalamic axons express Contactin-2 (CNTN2/TAG-1), a neuronal recognition molecule of the immunoglobulin superfamily involved in neurogenesis, neurite outgrowth, and fasciculation. TAG-1, which is expressed transiently by cortical pyramidal neurons during embryonic development, has been shown to be fundamental for axonal recognition, cellular migration, and neuronal proliferation in the developing cortex. Although Tag-1−/− mice do not exhibit any obvious defects in the corticofugal system, the role of TAG-1+ neurons during the development of the cortex remains elusive. We have generated a mouse model expressing EGFP under the Tag-1 promoter and encompassing the coding sequence of Diptheria Toxin subunit A (DTA) under quiescence with no effect on the expression of endogenous Tag-1. We show that while the line recapitulates the expression pattern of the molecule, it highlights an extended expression in the forebrain, including multiple axonal tracts and neuronal populations, both spatially and temporally. Crossing these mice to the Emx1-Cre strain, we ablated the vast majority of TAG-1+ cortical neurons. Among the observed defects were a significantly smaller cortex, a reduction of corticothalamic axons as well as callosal and commissural defects. Such defects are common in neurodevelopmental disorders, thus this mouse could serve as a useful model to study physiological and pathophysiological cortical development.
Highlights
The multilayered neocortex evolved in mammals and is responsible for a variety of higher functions, seen for the first time in this phylum
We generated the mouse strain Tag-1loxP−EGFP−loxP−DTA to further study the expression and role of TAG-1 in the developing embryo. In this transgenic mouse strain, EGFP is expressed under the promoter of Tag-1, while the transgene carries in frame the sequence coding for DTA in quiescence (Diptheria Toxin subunit A; Figure 1A)
Tag-1EGFP was detected in very few cells of the PP, with endogenous TAG-1 (Figures 2A–E), which increased by E12.5 (Figures 1B,C)
Summary
The multilayered neocortex evolved in mammals and is responsible for a variety of higher functions, seen for the first time in this phylum Among these higher cognitive functions is the integration of stimuli from different sensory modalities such as vision and olfaction, the control of motor commands, consciousness, decision-making, and in humans, speech. For these functions to take place, formation of axonal tracts that interconnect the neocortex with other brain areas or other systems of the central nervous system (CNS) and the organs responsible for the perception of stimuli is of tremendous importance. Several human syndromes have been attributed to or associated with phenotypic and functional abnormalities of cortical pyramidal neurons, such as in the case of people affected by the syndromes of the autistic spectrum or the Miller Dieker syndrome ( known as type I lissencephaly) (Takashima et al, 1981; Sheen et al, 2006a,b)
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