Transcription factor Lmo4 defines the shape of functional areas in developing cortices and regulates sensorimotor control

Abstract

Proper formation of the shape and size of cortical functional areas is essential for complex brain function, including sensory perception and motor control. Our previous work identified the transcription factor Lim domain only 4 (Lmo4), a regulator in calcium-dependent gene transcription, that has unique, region-specific expression in postnatal mouse cortices with high expression anteriorly and posteriorly but very low expression in between. Here we report that Lmo4 expression coincides with the timing of the development of the somatosensory barrel field. Lmo4 cortical deletion causes changes in expression patterns of cortical regional markers and results in rostro-medial shrinkage but not rostral or caudal shift of the somatosensory barrel subfield. Fine regulation of accurate shape of the barrel subfield by Lmo4, as well as Lmo4-mediated calcium-dependent gene expression, is critical for normal brain functions, as Lmo4-deficient mice display impaired sensorimotor performance. Moreover, even though Lmo4 has broad expression in the central nervous system, it plays a subtle role in the development of non-cortical regions. Our results reveal a new mechanism of cortical area formation and normal sensorimotor control that is regulated by genes with region-specific expression in the developing cortex.

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

“…Cited2 is expressed in the SVZ at E15.5 and, postnatally, by a restricted population of somatosensory CPN The transcriptional coregulator Cited2 [CBP/p300-interacting transactivator with glutamic acid/aspartic acid-rich C-terminal domain 2] is more highly expressed by CPN relative to other cortical projection neuron subpopulations [in particular, corticospinal motor neurons (CSMN)] in the developing neocortex, with peak differential expression at E18.5, the earliest time point at which CPN and CSMN can be purified by retrograde labeling (Molyneaux et al, 2009;Fig. 1A).…”

“…In situ hybridization was performed as previously described (Cederquist et al, 2013). The probes were synthesized as described previously: Cited2, Molyneaux et al (2009); Ror␤, ephrinA5, Allen Brain Atlas Resources (http://www.brain-map.org); EphA7, Mori et al (1995);Cadh8, Joshi et al (2008).…”

“…Lmo4 is a particularly compelling candidate to function in CPN of the motor cortex, and to interact with Cited2 at the motor-somatosensory cortex boundary. Lmo4 has reciprocal areal expression in the neocortex compared with Cited2, and has been shown to have areally restricted roles in neocortical projection neuron subtype identities and connectivity (Kashani et al, 2006;Joshi et al, 2008;Azim et al, 2009;Huang et al, 2009;Cederquist et al, 2013). Cited2 interacts genetically with Lmo4, and Lmo4 can partially functionally compensate for Cited2 in thymus development .…”

“…We previously identified a combinatorially expressed set of genes that both define CPN as a broad population and identify novel subpopulations of CPN during development (Molyneaux et al, 2009). Cited2 encodes a transcriptional coregulator that is significantly enriched in CPN over other cortical projection neuron subpopulations, with particularly high expression at early stages of CPN development (Molyneaux et al, 2009).…”

“…We previously identified a combinatorially expressed set of genes that both define CPN as a broad population and identify novel subpopulations of CPN during development (Molyneaux et al, 2009). Cited2 encodes a transcriptional coregulator that is significantly enriched in CPN over other cortical projection neuron subpopulations, with particularly high expression at early stages of CPN development (Molyneaux et al, 2009). CITED2 functions as a transcriptional coactivator by interacting with CBP/ p300 (Bhattacharya et al, 1999;Freedman et al, 2003), or as a transcriptional corepressor by competing with transcription factors for binding to CBP/p300 (Freedman et al, 2003;Lou et al, 2011).…”