Corticospinal neuron subpopulation-specific developmental genes prospectively indicate mature segmentally specific axon projection targeting

Sahni, Vibhu; Shnider, Sara J.; Jabaudon, Denis; Song, Janet; Itoh, Yoshio; Greig, Luciano C.; Macklis, Jeffrey D.

doi:10.1016/j.celrep.2021.109843

Cited by 30 publications

(114 citation statements)

References 94 publications

(162 reference statements)

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“…These results also suggest that Klhl14 functions while CSN BC-lat axons are extending in the cord, consistent with the time course of Klhl14 expression in CSN BC-lat : Klhl14 expression peaks early at E18.5 and P1, then gradually declines from P4 to P10, and expression is completely absent by P14 (Sahni et al, 2021). However, there remained the unlikely possibility that Klhl14 shRNA alters CSN BC-lat differentiation before their axons reach the cord, ultimately causing aberrant axon extension later at P4.…”

Section: Reduction In Klhl14 Function Causes Aberrant Csn Bc-lat Axon Targeting Beyond the Cervical Cordsupporting

confidence: 83%

“…In the accompanying study (Sahni et al, 2021), we identify that developing CSN subpopulations exhibit striking axon-targeting specificity in spinal white matter, and this establishes the foun-Figure 1. CSN are specified normally and project normally to the spinal cord in Crim1-null mice (A) Schematic outlining delineation of three segmentally specific CSN subpopulations (spatially distinct CSN BC-lat and interdigitated CSN BC-med and CSN TL ), indicating their molecular expression, axon extension, and axon collateralization, from the accompanying paper (Sahni et al, 2021). These CSN subpopulations are molecularly delineated during development and display persistent axon targeting before their final connectivity is established.…”

Section: Introductionmentioning

confidence: 54%

“…In this report and the accompanying paper (Sahni et al, 2021), we identify that distinct CSN subpopulations are molecularly specified during development to target distinct spinal segments at maturity. We identify molecular controls that distinguish during development anatomically, hodologically, and likely later functionally distinct CSN subpopulations, and they govern differential axon targeting of CSN at T2.…”

Section: Discussionmentioning

confidence: 74%

“…Klhl14 functions in postmitotic CSN BC-lat specifically when CSN axons are extending into the spinal cord Because CSN BC-lat and CSN medial do not exhibit different rates of axon extension (Sahni et al, 2021), it is not likely that Klhl14 limits CSN BC-lat axon extension to the cervical cord by inhibiting the rate of axon extension. We directly investigated this unlikely, but still theoretical, possibility.…”

Section: Reduction In Klhl14 Function Causes Aberrant Csn Bc-lat Axon Targeting Beyond the Cervical Cordmentioning

confidence: 99%

“…Klhl14 expression delineates Klhl14-positive CSN BC-lat (green) from Klhl14-negative CSN BC-med (purple); all CSN TL (red) are Klhl14 negative, and 95% ± 2% of CSN TL express Crim1 during early development. (B) Overlay of inverted and pseudocolored in situ hybridization images from the accompanying paper (Sahni et al, 2021) showing complementary expression of Klhl14 (green) and Crim1 (red) in cortex. The inset (Bʹ) shows Klhl14 is restricted to CSN BC-lat in lateral cortex.…”

Section: Introductionmentioning

confidence: 99%

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Crim1 and Kelch-like 14 exert complementary dual-directional developmental control over segmentally specific corticospinal axon projection targeting

Sahni

Itoh²,

Shnider³

et al. 2021

Cell Reports

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Section: Reduction In Klhl14 Function Causes Aberrant Csn Bc-lat Axon Targeting Beyond the Cervical Cordsupporting

confidence: 83%

Section: Introductionmentioning

confidence: 54%

Section: Discussionmentioning

confidence: 74%

Section: Reduction In Klhl14 Function Causes Aberrant Csn Bc-lat Axon Targeting Beyond the Cervical Cordmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Crim1 and Kelch-like 14 exert complementary dual-directional developmental control over segmentally specific corticospinal axon projection targeting

Sahni

Itoh²,

Shnider³

et al. 2021

Cell Reports

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Betz cells of the primary motor cortex

Nolan,

Scott,

Hof

et al. 2024

J of Comparative Neurology

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Betz cells, named in honor of Volodymyr Betz (1834–1894), who described them as “giant pyramids” in the primary motor cortex of primates and other mammalian species, are layer V extratelencephalic projection (ETP) neurons that directly innervate α‐motoneurons of the brainstem and spinal cord. Despite their large volume and circumferential dendritic architecture, to date, no single molecular criterion has been established that unequivocally distinguishes adult Betz cells from other layer V ETP neurons. In primates, transcriptional signatures suggest the presence of at least two ETP neuron clusters that contain mature Betz cells; these are characterized by an abundance of axon guidance and oxidative phosphorylation transcripts. How neurodevelopmental programs drive the distinct positional and morphological features of Betz cells in humans remains unknown. Betz cells display a distinct biphasic firing pattern involving early cessation of firing followed by delayed sustained acceleration in spike frequency and magnitude. Few cell type‐specific transcripts and electrophysiological characteristics are conserved between rodent layer V ETP neurons of the motor cortex and primate Betz cells. This has implications for the modeling of disorders that affect the motor cortex in humans, such as amyotrophic lateral sclerosis (ALS). Perhaps vulnerability to ALS is linked to the evolution of neural networks for fine motor control reflected in the distinct morphomolecular architecture of the human motor cortex, including Betz cells. Here, we discuss histological, molecular, and functional data concerning the position of Betz cells in the emerging taxonomy of neurons across diverse species and their role in neurological disorders.

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Amyotrophic lateral sclerosis represents corticomotoneuronal system failure

Eisen,

Vucic,

Kiernan

2024

Muscle and Nerve

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Several decades have passed since the anterograde corticomotoneuronal hypothesis for amyotrophic lateral sclerosis (ALS) was proposed. The intervening years have witnessed its emergent support based on anatomical, pathological, physiological, neuroimaging, and molecular biological studies. The evolution of an extensive corticomotoneuronal system appears restricted to the human species, with ALS representing a uniquely human disease. While some, very select non‐human primates have limited corticomotoneuronal projections, these tend to be absent in all other animals. From a general perspective, the early clinical features of ALS may be considered to reflect failure of the corticomotoneuronal system. The characteristic loss of skilled motor dexterity involving the limbs, and speech impairment through progressive bulbar dysfunction specifically involve those motor units having the strongest corticomotoneuronal projections. A similar explanation likely underlies the unique “split phenotypes” that have now been well characterized in ALS. Large Betz cells and other pyramidal corticomotoneuronal projecting neurons, with their extensive dendritic arborization, are particularly vulnerable to the elements of the ALS exposome such as aging, environmental stress and lifestyle changes. Progressive failure of the proteosome impairs nucleocytoplasmic shuffling and induces toxic but soluble TDP‐43 to aggregate in corticomotoneurons. Betz cell failure is further accentuated through dysfunction of its profuse dendritic arborizations. Clarification of system specific genomes and neural networks will likely promote the initiation of precision medicine approaches directed to support the key structure that underlies the neurological manifestations of ALS, the corticomotoneuronal system.

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Corticospinal neuron subpopulation-specific developmental genes prospectively indicate mature segmentally specific axon projection targeting

Cited by 30 publications

References 94 publications

Crim1 and Kelch-like 14 exert complementary dual-directional developmental control over segmentally specific corticospinal axon projection targeting

Crim1 and Kelch-like 14 exert complementary dual-directional developmental control over segmentally specific corticospinal axon projection targeting

Betz cells of the primary motor cortex

Amyotrophic lateral sclerosis represents corticomotoneuronal system failure

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