Cis-regulatory control of corticospinal system development and evolution

• Published in: Nature (London) 2012-06, Vol.486 (7401), p.74-79
• Main Authors: Shim, Sungbo, Kwan, Kenneth Y., Li, Mingfeng, Lefebvre, Veronique, Šestan, Nenad
• Format: Article
• Language: English
• Subjects: 631/208/182; 631/378/2571; 631/378/2583; Amniota; Animals; Axons - metabolism; Base Sequence; Binding Sites; Biological and medical sciences; DNA-Binding Proteins - genetics; Enhancer Elements, Genetic - genetics; Evolution; Evolution, Molecular; Fundamental and applied biological sciences. Psychology; Gene Expression Regulation, Developmental - genetics; Genetic aspects; Genetic Variation - genetics; Humanities and Social Sciences; Mice; Mice, Knockout; Mice, Transgenic; Molecular Sequence Data; multidisciplinary; Neocortex; Neocortex - cytology; Neocortex - embryology; Neocortex - metabolism; Nerve Tissue Proteins - genetics; Organ Specificity; Physiological aspects; Science; Science (multidisciplinary); SOXC Transcription Factors - metabolism; Spinal Cord - cytology; Spinal Cord - embryology; Spinal Cord - metabolism; Transcription factors; Vertebrates: nervous system and sense organs
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/nature11094

The co-emergence of a six-layered cerebral neocortex and its corticospinal output system is one of the evolutionary hallmarks of mammals. However, the genetic programs that underlie their development and evolution remain poorly understood. Here we identify a conserved non-exonic element (E4) that acts as a cortex-specific enhancer for the nearby gene Fezf2 (also known as Fezl and Zfp312 ), which is required for the specification of corticospinal neuron identity and connectivity. We find that SOX4 and SOX11 functionally compete with the repressor SOX5 in the transactivation of E4. Cortex-specific double deletion of Sox4 and Sox11 leads to the loss of Fezf2 expression, failed specification of corticospinal neurons and, independent of Fezf2 , a reeler -like inversion of layers. We show evidence supporting the emergence of functional SOX-binding sites in E4 during tetrapod evolution, and their subsequent stabilization in mammals and possibly amniotes. These findings reveal that SOX transcription factors converge onto a cis -acting element of Fezf2 and form critical components of a regulatory network controlling the identity and connectivity of corticospinal neurons. SOX transcription factors converge on a cortex-specific enhancer to regulate the dynamic, cell-type-specific expression of Fezf2 , a gene necessary for the formation of corticospinal system. Control of neocortical development The emergence and expansion of the neocortex has been crucial to the evolution of higher brain function in mammals. Neocortical layers differ in their projection patterns, with upper layers connecting to other cortical neurons and deeper layers projecting long distances to other brain areas and the spinal cord, but the genetic programs underlying these anatomical differences are unknown. Here, Shim et al . identify a conserved, cortex-specific enhancer that drives the Fezf2 -initiated specification program required for the production of the deep-layer, long-range projection neurons in the corticospinal tract. SOX transcription factors influence this enhancer through sites found to have emerged with tetrapods, modulating the regulatory network responsible for the corticospinal output system, an evolutionary hallmark of mammals.