FOXP2 exhibits projection neuron class specific expression, but is not required for multiple aspects of cortical histogenesis

Abstract

The expression patterns of the transcription factor FOXP2 in the developing mammalian forebrain have been described, and some studies have tested the role of this protein in the development and function of specific forebrain circuits by diverse methods and in multiple species. Clinically, mutations in FOXP2 are associated with severe developmental speech disturbances, and molecular studies indicate that impairment of Foxp2 may lead to dysregulation of genes involved in forebrain histogenesis. Here, anatomical and molecular phenotypes of the cortical neuron populations that express FOXP2 were characterized in mice. Additionally, Foxp2 was removed from the developing mouse cortex at different prenatal ages using two Cre-recombinase driver lines. Detailed molecular and circuit analyses were undertaken to identify potential disruptions of development. Surprisingly, the results demonstrate that Foxp2 function is not required for many functions that it has been proposed to regulate, and therefore plays a more limited role in cortical development than previously thought.

Modeling alcohol-induced neurotoxicity using human induced pluripotent stem cell-derived three-dimensional cerebral organoids

“…1E-b and 1E-c, respectively). CTIP2 identifies migrating neurons and deep cortical layers V/VI, whereas FOXP2 expression in the developing cortex is restricted to subpopulations of post-mitotic neurons in deep cortical layers (V/VI) 73,93 . These elaborate cellular laminar organization and architectures are very similar to what was observed in human brains [94][95][96] .…”

FOXP transcription factors in vertebrate brain development, function, and disorders

“…The mammalian neocortex (referred to as "cortex" in this review) is a dorsal telencephalon-derived brain structure arising from the ventricular zone (VZ), where radial glia divide to eventually produce postmitotic neurons of the cortical plate (CP) and later the mature six-layered cortex. In mice, faint mRNA signals for Foxp1/2 appear in the VZ by embryonic day (E) 12.5 (Ferland et al, 2003), but studies conflict over their protein expression here, with some reporting expression (Braccioli et al, 2017;Pearson et al, 2018;Tsui, Vessey, Tomita, Kaplan, & Miller, 2013) and others reporting absence (Ferland et al, 2003;Kast, Lanjewar, Smith, & Levitt, 2019). By E16.5, both are expressed in the CP at the protein level (Ferland et al, 2003).…”

“…In one study, Foxp2 knockdown by IUE of shRNA at E13/14 impaired the transition of radial glia into intermediate progenitors and neurons, and also impaired the migration of neurons into the upper layers of the cortex (Tsui et al, 2013). However, crosses of Foxp2 flox/flox mice with cortical Cre-driver mice have generated cKO mice with normal cortical size, neuronal density, layering, and projections (Co, Hickey, Kulkarni, Harper, & Konopka, 2019;French et al, 2018;Kast et al, 2019;Medvedeva et al, 2018). These discrepancies could result from molecular compensation by other Foxp genes upon genetic Foxp2 deletion, but notably, Foxp1/4 transcripts were not upregulated in cortical neurons in an RNA-seq study of cortical Foxp2 cKO mice (Co et al, 2019).…”

Genetic dissection of glutamatergic neuron subpopulations and developmental trajectories in the cerebral cortex

“…The forkhead/winged helix transcription factor, Foxp2 , is expressed in many CT neurons from postmitotic stage to mature cortex, and transiently expressed in a minor subset of ET neurons in the first postnatal week 64, 65 . We characterized a Foxp2-IRES-Cre KI line 66 by systemic injection of Cre dependent AAV9-DIO-GFP in 2 month old mice to reveal its brain-wide cell distribution pattern.…”