Cited2 Regulates Neocortical Layer II/III Generation and Somatosensory Callosal Projection Neuron Development and Connectivity

Abstract

The neocortex contains hundreds to thousands of distinct subtypes of precisely connected neurons, allowing it to perform remarkably complex tasks of high-level cognition. Callosal projection neurons (CPN) connect the cerebral hemispheres via the corpus callosum, integrating cortical information and playing key roles in associative cognition. CPN are a strikingly diverse set of neuronal subpopulations, and development of this diversity requires precise control by a complex, interactive set of molecular effectors. We have found that the transcriptional coregulator Cited2 regulates and refines two stages of CPN development. Cited2 is expressed broadly by progenitors in the embryonic day 15.5 subventricular zone, during the peak of superficial layer CPN birth, with a progressive postmitotic refinement in expression, becoming restricted to CPN of the somatosensory cortex postnatally. We generated progenitor-stage and postmitotic forebrain-specific Cited2 conditional knock-out mice, using the Emx1-Cre and NEX-Cre mouse lines, respectively. We demonstrate that Cited2 functions in progenitors, but is not necessary postmitotically, to regulate both (1) broad generation of layer II/III CPN and (2) acquisition of precise area-specific molecular identity and axonal/dendritic connectivity of somatosensory CPN. This novel CPN subtypespecific and area-specific control from progenitor action of Cited2 adds yet another layer of complexity to the multistage developmental regulation of neocortical development.

Evolutionary Gain of Dbx1 Expression Drives Subplate Identity in the Cerebral Cortex

“…However, as in the case of Tbr1, a feedback control on patterning centers was also observed, leaving open the possibility that some of the cell fate changes depend on patterning centers and thus through an intermediate progenitor state (Elsen et al, 2013;Bedogni et al, 2010). Very recent studies discriminated the postmitotic role of transcription factors (TFs) expressed in both progenitors and neurons using similar genetic tools based on Nex:Cre expression (Wu et al, 2005;Alfano et al, 2014;Golonzhka et al, 2015;Zembrzycki et al, 2015;Kazdoba et al, 2012;Fame et al, 2016;Nakamura et al, 2016) in controlling area-specific properties and laminar fate. Together, these reports (Arlotta and Hobert, 2015;De la Rossa et al, 2013) and our work underlie the rising concept of the key role of TFs expressed in postmitotic neurons as potent cell fate determinants.…”

Evolution of connections and cell types: integrating diffusion MR tractography with gene expression data highlights increased cortico-cortical projections in primates

“…Spatial resolution was 0.13 × 0.13 × 0.17 mm for mice, and 0.23 × 0.23 × 0.28 mm for marmoset. Sixty diffusion-weighted measurements (b = 4,000 sec/mm 2 ) and one non diffusion-weighted (b = 0) measurement were acquired, with δ= 12.0 msec, Δ = 24.0 msec as previously described (Rosen et al, 2013;Fame et al, 2016;Kanamaru et al, 2017). The total acquisition time was about 2 hours and 10 minutes for each imaging session.…”

High angular resolution diffusion MRI reveals conserved and deviant programs in the paths that guide human cortical circuitry

“…Considerable work has been conducted on radial glial development, pioneer, as well as callosal development in model organisms such as mice, rats, monkeys, and cats (Wise and Jones, 1976;Marin-Padilla, 1978;Innocenti, 1981;O'Leary et al, 1981;Ivy and Killackey, 1982;Silver et al, 1982;Luskin and Shatz, 1985;Berbel and Innocenti, 1988;Mrzljak et al, 1988;Voigt, 1989;Mrzljak et al, 1990;Lent et al, 1990;LaMantia and Rakic, 1990;Aggoun-Zouaoui and Innocenti, 1994;Tessier-Lavigne and Goodman, 1996;Richards et al, 1997;Shu and Richards, 2001;Richards, 2002Richards, , 2012Unni et al, 2012;Fame, MacDonald, et al, 2016;Gobius et al, 2016;Niquille et al, 2019), as well as humans (Rakic and Yakovlev, 1968;Kostovic and Krmpotic, 1976;Kostovic and Rakic, 1990;Marin-Padilla, 1992;Kier and Truwit, 1996;deAzevedo et al 1997;Rados et al 2006;Ren et al, 2006;Huang et al 2006;Huang et al 2009). Yet, we still know very little about the basic developmental timeline of radial glia, pioneer development, and cortical association pathways in humans, and which developmental processes are conserved or variant between humans and other species.…”