TY - JOUR
T1 - Temporal controls over inter-areal cortical projection neuron fate diversity
AU - Klingler, Esther
AU - Tomasello, Ugo
AU - Prados, Julien
AU - Kebschull, Justus M.
AU - Contestabile, Alessandro
AU - Galiñanes, Gregorio L.
AU - Fièvre, Sabine
AU - Santinha, Antonio
AU - Platt, Randal
AU - Huber, Daniel
AU - Dayer, Alexandre
AU - Bellone, Camilla
AU - Jabaudon, Denis
N1 - Publisher Copyright:
© 2021, The Author(s), under exclusive licence to Springer Nature Limited.
PY - 2021/11/18
Y1 - 2021/11/18
N2 - Interconnectivity between neocortical areas is critical for sensory integration and sensorimotor transformations1–6. These functions are mediated by heterogeneous inter-areal cortical projection neurons (ICPN), which send axon branches across cortical areas as well as to subcortical targets7–9. Although ICPN are anatomically diverse10–14, they are molecularly homogeneous15, and how the diversity of their anatomical and functional features emerge during development remains largely unknown. Here we address this question by linking the connectome and transcriptome in developing single ICPN of the mouse neocortex using a combination of multiplexed analysis of projections by sequencing16,17 (MAPseq, to identify single-neuron axonal projections) and single-cell RNA sequencing (to identify corresponding gene expression). Focusing on neurons of the primary somatosensory cortex (S1), we reveal a protracted unfolding of the molecular and functional differentiation of motor cortex-projecting (M ⃗ ) ICPN compared with secondary somatosensory cortex-projecting (S 2 ⃗ ) ICPN. We identify SOX11 as a temporally differentially expressed transcription factor in M ⃗ versus S 2 ⃗ ICPN. Postnatal manipulation of SOX11 expression in S1 impaired sensorimotor connectivity and disrupted selective exploratory behaviours in mice. Together, our results reveal that within a single cortical area, different subtypes of ICPN have distinct postnatal paces of molecular differentiation, which are subsequently reflected in distinct circuit connectivities and functions. Dynamic differences in the expression levels of a largely generic set of genes, rather than fundamental differences in the identity of developmental genetic programs, may thus account for the emergence of intra-type diversity in cortical neurons.
AB - Interconnectivity between neocortical areas is critical for sensory integration and sensorimotor transformations1–6. These functions are mediated by heterogeneous inter-areal cortical projection neurons (ICPN), which send axon branches across cortical areas as well as to subcortical targets7–9. Although ICPN are anatomically diverse10–14, they are molecularly homogeneous15, and how the diversity of their anatomical and functional features emerge during development remains largely unknown. Here we address this question by linking the connectome and transcriptome in developing single ICPN of the mouse neocortex using a combination of multiplexed analysis of projections by sequencing16,17 (MAPseq, to identify single-neuron axonal projections) and single-cell RNA sequencing (to identify corresponding gene expression). Focusing on neurons of the primary somatosensory cortex (S1), we reveal a protracted unfolding of the molecular and functional differentiation of motor cortex-projecting (M ⃗ ) ICPN compared with secondary somatosensory cortex-projecting (S 2 ⃗ ) ICPN. We identify SOX11 as a temporally differentially expressed transcription factor in M ⃗ versus S 2 ⃗ ICPN. Postnatal manipulation of SOX11 expression in S1 impaired sensorimotor connectivity and disrupted selective exploratory behaviours in mice. Together, our results reveal that within a single cortical area, different subtypes of ICPN have distinct postnatal paces of molecular differentiation, which are subsequently reflected in distinct circuit connectivities and functions. Dynamic differences in the expression levels of a largely generic set of genes, rather than fundamental differences in the identity of developmental genetic programs, may thus account for the emergence of intra-type diversity in cortical neurons.
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U2 - 10.1038/s41586-021-04048-3
DO - 10.1038/s41586-021-04048-3
M3 - Article
C2 - 34754107
AN - SCOPUS:85118610560
SN - 0028-0836
VL - 599
SP - 453
EP - 457
JO - Nature
JF - Nature
IS - 7885
ER -