Neuronal Subtype-Specific Genes that Control Corticospinal Motor Neuron Development In Vivo

Abstract

Within the vertebrate nervous system, the presence of many different lineages of neurons and glia complicates the molecular characterization of single neuronal populations. In order to elucidate molecular mechanisms underlying the specification and development of corticospinal motor neurons (CSMN), we purified CSMN at distinct stages of development in vivo and compared their gene expression to two other pure populations of cortical projection neurons: callosal projection neurons and corticotectal projection neurons. We found genes that are potentially instructive for CSMN development, as well as genes that are excluded from CSMN and are restricted to other populations of neurons, even within the same cortical layer. Loss-of-function experiments in null mutant mice for Ctip2 (also known as Bcl11b), one of the newly characterized genes, demonstrate that it plays a critical role in the development of CSMN axonal projections to the spinal cord in vivo, confirming that we identified central genetic determinants of the CSMN population.

Altered proliferative ability of neuronal progenitors in PlexinA1 mutant mice

“…5A–D). We also observed a significantly reduced number of Ctip2 (early‐born)‐ and Cux1 (late‐born)‐positive neurons (Arlotta et al, 2005; Cubelos et al, 2008) in the developing cortex at E18.5 (Ctip2: PlexinA1 +/ + 41.93 ± 15.7, PlexinA1 −/− 28.41 ± 6.7 [ P  < 0.3]; Cux1: PlexinA1 +/ + 82.07 ± 6.4, PlexinA1 −/− 58.24 ± 4.3 [ P  < 0.005]; Fig. 5E–I).…”

“…sc‐13024, RRID: AB_2261231) raised against amino acids 1111–1332 of CDP/Cux1 of mouse origin. CDP immunohistochemistry of wild‐type embryonic mouse forebrain sections specifically labels upper layer pyramidal neurons (Arlotta et al, 2005; Yeh et al, 2014). …”

The determination of projection neuron identity in the developing cerebral cortex

“…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 expression domain of Fezf2 (which is most prominent in cortex and hippocampus, but is also found in a subset of hypothalamic cells) is much more limited than that of Ctip2, which is broadly expressed in the striatum, olfactory bulb and other regions.…”

“…The expression domain of Fezf2 (which is most prominent in cortex and hippocampus, but is also found in a subset of hypothalamic cells) is much more limited than that of Ctip2, which is broadly expressed in the striatum, olfactory bulb and other regions. However, within the cortex, both Fezf2 and Ctip2 are expressed by subcortically projecting neurons in layer 5 and in the corticothalamic projection neurons of layer 6 [12,32,34]. Importantly, Ctip2 expression is lost in the cortices of Fezf2 mutant mice (but not in other brain regions) [12,32], whereas the converse is not the case: Ctip2 mutants continue to express Fezf2 (J.D.…”

“…Indeed, the ectopic expression of Satb2 in neurons markedly reduces the fraction of cells that express Ctip2 [49,50], and alters the projections of deep layer neurons, such that the axons of electroporated cells fail to extend past the cerebral peduncle [50]. This axonal phenotype is reminiscent of that observed in Ctip2 −/− brains [34], suggesting that the ectopic expression of Satb2 might alter the fate of deep layer neurons by regulating Ctip2 expression.…”