Cited2 Regulates Neocortical Layer II/III Generation and Somatosensory Callosal Projection Neuron Development and Connectivity.
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 subtype-specific and area-specific control from progenitor action of Cited2 adds yet another layer of complexity to the multistage developmental regulation of neocortical development.



This study identifies Cited2 as a novel subtype-specific and area-specific control over development of distinct subpopulations within the broad population of callosal projection neurons (CPN), whose axons connect the two cerebral hemispheres via the corpus callosum (CC). Currently, how the remarkable diversity of CPN subtypes is specified, and how they differentiate to form highly precise and specific circuits, are largely unknown. We found that Cited2 functions within subventricular zone progenitors to both broadly regulate generation of superficial layer CPN throughout the neocortex, and to refine precise area-specific development and connectivity of somatosensory CPN. Gaining insight into molecular development and heterogeneity of CPN will advance understanding of both diverse functions of CPN and of the remarkable range of neurodevelopmental deficits correlated with CPN/CC development.
Department of Stem Cell and Regenerative Biology, Center for Brain Science, and Harvard Stem Cell Institute, Harvard University, Cambridge, Massachusetts 02138.
Ryann M
0000-0002-8244-2624
RM
Fame
Department of Stem Cell and Regenerative Biology, Center for Brain Science, and Harvard Stem Cell Institute, Harvard University, Cambridge, Massachusetts 02138.
Jessica L
0000-0002-9111-5756
JL
MacDonald
Developmental and Stem Cell Biology Division, Victor Chang Cardiac Research Institute, Darlinghurst, Sydney, New South Wales, 2052 Australia, Faculties of Medicine and Science, University of New South Wales, Kensington, Sydney, New South Wales, 2052 Australia.
Sally L
0000-0002-2069-7349
SL
Dunwoodie
Division of Newborn Medicine, Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts 02115, Fetal-Neonatal Neuroimaging and Developmental Science Center, Boston, Massachusetts 02115, and Athinoula A. Martinos Center for Biomedical Imaging, Charlestown, Massachusetts 02129.
Emi
E
Takahashi
Department of Stem Cell and Regenerative Biology, Center for Brain Science, and Harvard Stem Cell Institute, Harvard University, Cambridge, Massachusetts 02138, jeffrey_macklis@harvard.edu.
Jeffrey D
JD
Macklis
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D003337:Corpus Callosum / Q000502:physiology*; D004622:Embryo, Mammalian; D005260:Female; D007839:Functional Laterality; D018507:Gene Expression Regulation, Developmental / Q000235:genetics*; D060588:LIM Domain Proteins / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D004676:Myelin Basic Protein / Q000235:genetics / Q000378:metabolism; D019579:Neocortex / Q000166:cytology / Q000000981:diagnostic imaging / Q000196:embryology / Q000254:growth & development; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D009434:Neural Pathways / Q000502:physiology*; D009474:Neurons / Q000502:physiology* / Q000648:ultrastructure; D000071841:PAX6 Transcription Factor / Q000378:metabolism; D018809:Proliferating Cell Nuclear Antigen / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D013003:Somatosensory Cortex / Q000166:cytology / Q000196:embryology / Q000254:growth & development; D020825:T-Box Domain Proteins / Q000378:metabolism; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*
D048868:Adaptor Proteins, Signal Transducing; C110087:Cited2 protein, mouse; C491198:Eomes protein, mouse; D060588:LIM Domain Proteins; C491976:Lmo4 protein, mouse; C499047:Mbp protein, mouse; D004676:Myelin Basic Protein; D009419:Nerve Tissue Proteins; D000071841:PAX6 Transcription Factor; C000605732:Pax6 protein, mouse; D018809:Proliferating Cell Nuclear Antigen; D012097:Repressor Proteins; D020825:T-Box Domain Proteins; D015534:Trans-Activators
arealization; callosum; neocortex; neuronal differentiation; somatosensory