Molecular Controls that Direct Subtype-Specification, Development, and Diversity of Cortical Projection Neurons

 

Molecular Controls that Direct Subtype-Specification, Development, and Diversity of Cortical Projection Neurons

Our lab is interested in elucidation of molecular controls that direct subtype-specific specification, development, and diversity of cortical projection neurons, in particular corticospinal motor neurons, callosal, corticothalamic, and corticostriatal, and diverse sub-subtypes with unique circuitry. We innovatively adapted FACS-based neuronal purification for transcriptional analysis of small homogeneous samples of multiple hodological subtypes of cortical projection neurons at critical developmental stages. Loss- and gain-of-function analyses for multiple identified genes and molecules reveal a nested “molecular logic” of progenitor-stage and post-mitotic, areally specific, combinatorial molecular-genetic controls over precise development of key cortical and other forebrain projection neuron populations. This work contributes to understanding development, organization, function, and evolution of cortical circuitry, and toward directed differentiation of neural progenitors or ES/iPS cells, regeneration, reprogramming, induced neurogenesis, and identification of disease genes.

 

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Selected publications

Cortical Output Projection Neuron Molecular Development, Diversity and Disease

  • Galazo, M. J., Emsley, J. G. & Macklis, J. D. Corticothalamic Projection Neuron Development beyond Subtype Specification: Fog2 and Intersectional Controls Regulate Intraclass Neuronal Diversity. Neuron 91, 90–106 (2016). Pubmed

  • Woodworth, M. B. et al. Ctip1 Regulates the Balance between Specification of Distinct Projection Neuron Subtypes in Deep Cortical Layers. Cell Rep 15, 999–1012 (2016). Pubmed

  • Cederquist, G. Y., Azim, E., Shnider, S. J., Padmanabhan, H. & Macklis, J. D. Lmo4 establishes rostral motor cortex projection neuron subtype diversity. J Neurosci 33, 6321–6332 (2013). Pubmed

  • Custo Greig, L. F., Woodworth, M. B., Galazo, M. J., Padmanabhan, H. & Macklis, J. D. Molecular logic of neocortical projection neuron specification, development and diversity. Nat Rev Neurosci 14, 755–769 (2013). Pubmed

  • Azim, E., Jabaudon, D., Fame, R. M. & Macklis, J. D. SOX6 controls dorsal progenitor identity and interneuron diversity during neocortical development. Nat Neurosci 12, 1238–1247 (2009). Pubmed

  • Lai, T. et al. SOX5 controls the sequential generation of distinct corticofugal neuron subtypes. Neuron 57, 232–247 (2008). Pubmed

  • Ozdinler, P. H. & Macklis, J. D. IGF-I specifically enhances axon outgrowth of corticospinal motor neurons. Nat Neurosci 9, 1371–1381 (2006). Pubmed

  • Arlotta, P. et al. Neuronal subtype-specific genes that control corticospinal motor neuron development in vivo. Neuron 45, 207–221 (2005). Pubmed

  • Molyneaux, B. J., Arlotta, P., Hirata, T., Hibi, M. & Macklis, J. D. Fezl is required for the birth and specification of corticospinal motor neurons. Neuron 47, 817–831 (2005). Pubmed

Inter-hemispheric Callosal Projection Neuron Molecular Development, Diversity, and Disease

  • Greig, L. C., Woodworth, M. B., Greppi, C. & Macklis, J. D. Ctip1 controls acquisition of sensory area identity and establishment of sensory input fields in the developing neocortex. Neuron 90, 261–277 (2016). Pubmed

  • Woodworth, M. B. et al. Ctip1 Regulates the Balance between Specification of Distinct Projection Neuron Subtypes in Deep Cortical Layers. Cell Rep 15, 999–1012 (2016). Pubmed

  • Fame, R. M., MacDonald, J. L., Dunwoodie, S. L., Takahashi, E. & Macklis, J. D. Cited2 regulates neocortical layer II/III generation and somatosensory callosal projection neuron development and connectivity. J Neurosci 36, 6403–6419 (2016). Pubmed

  • Kishi, N. et al. Reduction of aberrant NF-κB signalling ameliorates Rett syndrome phenotypes in Mecp2-null mice. Nat Commun 7, 10520 (2016). Pubmed

  • Fame, R. M., MacDonald, J. L. & Macklis, J. D. Development, specification, and diversity of callosal projection neurons. Trends Neurosci 34, 41–50 (2011). Pubmed

  • Molyneaux, B. J. et al. Novel subtype-specific genes identify distinct subpopulations of callosal projection neurons. J Neurosci 29, 12343–12354 (2009). Pubmed