Transcriptional control of motor pool formation and motor circuit connectivity by the LIM-HD protein Isl2
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eLife assessment
This paper will be of interest to developmental biologists who study the gene regulatory mechanisms necessary for neuronal identity and circuit assembly. The study presents important findings regarding the role of the LIM homeodomain transcription factor Isl2 in the development of spinal motor neurons. While the importance of Isl2 for the acquisition of axial and visceral motor neuron development was already described in the literature, the data convincingly describe an additional role in the differentiation of a subset of limb-innervating motor neurons.
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Abstract
The fidelity of motor control requires the precise positional arrangement of motor pools and the establishment of synaptic connections between them. During neural development in the spinal cord, motor nerves project to specific target muscles and receive proprioceptive input from these muscles via the sensorimotor circuit. LIM-homeodomain transcription factors are known to play a crucial role in successively restricting specific motor neuronal fates. However, their exact contribution to limb-based motor pools and locomotor circuits has not been fully understood. To address this, we conducted an investigation into the role of Isl2, a LIM-homeodomain transcription factor, in motor pool organization. We found that deletion of Isl2 led to the dispersion of motor pools, primarily affecting the median motor column (MMC) and lateral motor column (LMC) populations. Additionally, hindlimb motor pools lacked Etv4 expression, and we observed reduced terminal axon branching and disorganized neuromuscular junctions in Isl2 -deficient mice. Furthermore, we performed transcriptomic analysis on the spinal cords of Isl2- deficient mice and identified a variety of downregulated genes associated with motor neuron (MN) differentiation, axon development, and synapse organization in hindlimb motor pools. As a consequence of these disruptions, sensorimotor connectivity and hindlimb locomotion were impaired in Isl2- deficient mice. Taken together, our findings highlight the critical role of Isl2 in organizing motor pool position and sensorimotor circuits in hindlimb motor pools. This research provides valuable insights into the molecular mechanisms governing motor control and its potential implications for understanding motor-related disorders in humans.
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eLife assessment
This paper will be of interest to developmental biologists who study the gene regulatory mechanisms necessary for neuronal identity and circuit assembly. The study presents important findings regarding the role of the LIM homeodomain transcription factor Isl2 in the development of spinal motor neurons. While the importance of Isl2 for the acquisition of axial and visceral motor neuron development was already described in the literature, the data convincingly describe an additional role in the differentiation of a subset of limb-innervating motor neurons.
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Reviewer #1 (Public Review):
In mammals, limb-innervating motor neurons are found at brachial and lumbar levels of the spinal cord. While it has been known for a long time that a combination of transcription factors (e.g., Hox, FoxP1) is necessary for the development of these motor neurons, it remains unclear whether similar or distinct transcriptional programs operate in brachial and lumbar motor neurons. This study advances our understanding of how motor pools are specified in the lumbar region. The authors found, in hindlimb-innervation motor neurons, that the LIM homeodomain transcription factor Isl2 is selectively required for motor pool organization, neuromuscular connectivity, and hindlimb locomotion.
Major conclusions include:
1. Settling position of motor neurons is impaired in Isl2 mutant mice; MMC neurons at all levels and …
Reviewer #1 (Public Review):
In mammals, limb-innervating motor neurons are found at brachial and lumbar levels of the spinal cord. While it has been known for a long time that a combination of transcription factors (e.g., Hox, FoxP1) is necessary for the development of these motor neurons, it remains unclear whether similar or distinct transcriptional programs operate in brachial and lumbar motor neurons. This study advances our understanding of how motor pools are specified in the lumbar region. The authors found, in hindlimb-innervation motor neurons, that the LIM homeodomain transcription factor Isl2 is selectively required for motor pool organization, neuromuscular connectivity, and hindlimb locomotion.
Major conclusions include:
1. Settling position of motor neurons is impaired in Isl2 mutant mice; MMC neurons at all levels and LMC neurons at the lumbar level.
2. Isl2 controls Pea3 expression in lumbar motor pools.
3. A transcriptomic analysis uncovered multiple Isl2 downstream target genes.
4. The connectivity and function of hindlimb motor pools are disrupted in Isl2 mutant mice.The conclusions are supported by experimental evidence.
Strengths:
The study fills an important knowledge gap by uncovering a developmental role for the LIM homeodomain transcription factor Isl2 in hindlimb motor pools.
The authors employ an impressive array of genetic, molecular, behavioral, and electrophysiological methods to comprehensively characterize the function of Isl2 in spinal motor neurons.
Weaknesses:
Most experiments have been conducted in Isl2 global KO mice, raising the issue of cell autonomy. However, the key conclusion of Isl2 controlling Pea3 expression has been independently confirmed in animals lacking Isl2 activity selectively in motor neurons (Olig2Cre line).
The mechanistic details downstream of Isl2 remain elusive.
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Reviewer #2 (Public Review):
The manuscript aims to define in detail the role of the LIM homeodomain transcription factor isl2 in the acquisition of cardinal spinal motor neuron identities. The authors, by using a number of different and complementary techniques, analyze Isl2 expression in motor neuron subtypes and describe the consequences of its loss on motor neuron generation, positional organization, sensorimotor connectivity, and function. While the importance of Isl2 for the development of axial and visceral motor neurons was already known, the data presented here convincingly show that Isl2 has a previously unappreciated role in controlling differentiation of a subset of motor neurons innervating proximal hindlimb muscles by regulating the expression of the ETS transcription factor Pae3.
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Reviewer #3 (Public Review):
The authors perform a thorough investigation of the role of Islet2 in the specification of lumbar motor pools. They use a number of approaches, including RNA-seq, behavioral testing, and imaging to establish a role for this transcription factor (TF) in the organization and axonal and dendritic morphology primarily of the Gl motor pool. The experiments are clear, well-presented, and convincing. Concerns about this work stem from the fact that the authors use a null mouse instead of a conditional. While this is not so problematic when examining MN properties such as organization, it makes data on connectivity and behavior hard to interpret. Since the authors perform one experiment with the conditional mouse (showing Pea3 downregulation), it is a bit puzzling that they did not use these mice for the rest of the …
Reviewer #3 (Public Review):
The authors perform a thorough investigation of the role of Islet2 in the specification of lumbar motor pools. They use a number of approaches, including RNA-seq, behavioral testing, and imaging to establish a role for this transcription factor (TF) in the organization and axonal and dendritic morphology primarily of the Gl motor pool. The experiments are clear, well-presented, and convincing. Concerns about this work stem from the fact that the authors use a null mouse instead of a conditional. While this is not so problematic when examining MN properties such as organization, it makes data on connectivity and behavior hard to interpret. Since the authors perform one experiment with the conditional mouse (showing Pea3 downregulation), it is a bit puzzling that they did not use these mice for the rest of the experiments.
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