Celsr3 Inactivation in the Brainstem Impairs Rubrospinal Tract Development and Mouse Behaviors in Motor Coordination
Boli Chen1, Fuxiang Li1, Bin Jia1
1Guangdong-Hongkong-Macau CNS Regeneration Institute of Jinan University, Key Laboratory of CNS Regeneration (Jinan University)-Ministry of Education, Jinan University, Huangpu Avenue West 601, Guangzhou, 510632, People's Republic of China.
Abstract:
Inactivation of Celsr3 in the forebrain results in defects of longitudinal axonal tracts such as the corticospinal tract. In this study, we inactivated Celsr3 in the brainstem using En1-Cre mice (Celsr3 cKO) and analyzed axonal and behavioral phenotypes. Celsr3 cKO animals showed an 83% reduction of rubrospinal axons and 30% decrease of corticospinal axons in spinal segments, associated with increased branching of dopaminergic fibers in the ventral horn. Decreases of spinal motoneurons, neuromuscular junctions, and electromyographic signal amplitude of the biceps were also found in mutant animals. Mutant mice had impaired motor coordination and defective response to heavy mechanical stimulation, but no disability in walking and food pellet handling. Transsynaptic tracing demonstrated that rubrospinal axons synapse on spinal neurons in the deep layer of the dorsal horn, and mechanical stimulation of hindpaws induced strong calcium signal of red nuclei in control mice, which was less prominent in mutant mice. In conclusion, Celsr3 regulates development of spinal descending axons and the motor network in cell and non-cell autonomous manners, and the maturation of the rubrospinal system is required for motor coordination and response to mechanical stimulation.
Insights
Cadherinueslike family member 3 (Celsr3) inactivation in the brainstem disrupts descending spinal axons, impacting motor coordination and response to mechanical stimuli. This study reveals Celsr3
Area of Science:
- Neuroscience
- Developmental Biology
- Genetics
Background:
- Celsr3 is crucial for axonal tract development in the forebrain.
- The role of Celsr3 in brainstem-spinal cord circuitry is not well understood.
Purpose of the Study:
- To investigate the function of Celsr3 in brainstem-mediated descending motor pathways.
- To analyze the impact of Celsr3 inactivation on axonal development and motor behavior.
Main Methods:
- Conditional knockout (cKO) of Celsr3 in En1-Cre expressing brainstem neurons.
- Analysis of axonal tracts (rubrospinal, corticospinal) using immunohistochemistry.
- Assessment of spinal motoneurons, neuromuscular junctions, and electromyography.
- Behavioral testing for motor coordination and sensory response.
- Transsynaptic tracing and in vivo calcium imaging.
Main Results:
- Celsr3 cKO mice exhibited significant reductions in rubrospinal (83%) and corticospinal (30%) axons.
- Mutant animals showed decreased spinal motoneurons and neuromuscular junction integrity.
- Impaired motor coordination and defective response to mechanical stimulation were observed.
- Rubrospinal axons were found to synapse on dorsal horn neurons, crucial for mechanical response.
Conclusions:
- Celsr3 plays a vital role in the development of descending spinal axons from the brainstem.
- Celsr3 regulates motor network formation through cell-autonomous and non-cell-autonomous mechanisms.
- Proper maturation of the rubrospinal system, regulated by Celsr3, is essential for motor coordination and mechanical sensory processing.
