TY - JOUR
T1 - Cited2 regulates neocortical layer II/III generation and somatosensory callosal projection neuron development and connectivity
AU - Fame, Ryann M.
AU - MacDonald, Jessica L.
AU - Dunwoodie, Sally L.
AU - Takahashi, Emi
AU - Macklis, Jeffrey D.
N1 - Funding Information:
This work was supported by grants from the National Institutes of Health (R37 NS41590 and NS093376, with additional infrastructure support by NS45523, NS49553, and NS075672), the Jane and Lee Seidman Fund, the Emily and Robert Perlstein Fund, and the United Sydney Association (to J.D.M.); a National Science Foundation Graduate Research Fellowship Program fellowship and National Institutes of Health predoctoral National Research Service Award Fellowship F31 NS073163 (to R.M.F.); the Eunice Shriver Kennedy National Institute of Child Health and Human Development (NIH R01HD078561, R21HD069001; to E.T.); and a National Health and Medical Research Council Senior Research Fellowship (ID1042002; to S.L.D.). We thank members of the Macklis laboratory for thoughtful discussions and input, and Lincoln Pasquina, Ryan Richardson, Ben Noble, and Ioana Florea for technical assistance. Wethank Professor Klaus-Armin Nave (Max Planck Institute of Experimental Medicine, Goettingen, Germany) for generously providing the NEX-Cre mice.
Publisher Copyright:
© 2016 the authors.
PY - 2016/6/15
Y1 - 2016/6/15
N2 - 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.
AB - 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.
KW - Arealization
KW - Callosum
KW - Neocortex
KW - Neuronal differentiation
KW - Somatosensory
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UR - http://www.scopus.com/inward/citedby.url?scp=84974834788&partnerID=8YFLogxK
U2 - 10.1523/JNEUROSCI.4067-15.2016
DO - 10.1523/JNEUROSCI.4067-15.2016
M3 - Article
C2 - 27307230
AN - SCOPUS:84974834788
SN - 0270-6474
VL - 36
SP - 6403
EP - 6419
JO - Journal of Neuroscience
JF - Journal of Neuroscience
IS - 24
ER -