Scientific Understanding of Consciousness
Motor Neurons Relay Neural Commands to Drive Skeletal Muscle Movements
Science 14 March 2014: Vol. 343 no. 6176 pp. 1264-1266
Dlk1 Promotes a Fast Motor Neuron Biophysical Signature Required for Peak Force Execution
Daniel Müller, Pitchaiah Cherukuri, Kristine Henningfeld, Chor Hoon Poh, Lars Wittler, Phillip Grote, Oliver Schlüter, Jennifer Schmidt, Jorge Laborda, Steven R. Bauer, Robert M. Brownstone, Till Marquardt
Developmental Neurobiology Laboratory, European Neuroscience Institute (ENI-G), Grisebachstraße 5, 37077 Göttingen, Germany.
Institute of Developmental Biochemistry, University Medical Center Göttingen, Justus-von-Liebig-Weg 11, 37077 Göttingen, Germany.
Center for Nanoscale Microscopy and Molecular Physiology of the Brain, Göttingen, Germany.
Department of Developmental Genetics, Max-Planck Institute for Molecular Genetics, Ihnestraße 63-73, 14195 Berlin, Germany.
Molecular Neurobiology Laboratory, ENI-G, Grisebachstraße 5, 37077 Göttingen, Germany.
6Department of Biological Sciences, University of Illinois at Chicago, 900 South Ashland Avenue, MBRB 4210 Chicago, IL 60607, USA.
Departament of Inorganic and Organic Chemistry and Biochemistry, University of Castilla–La Mancha Medical School, 02006 C/Almansa 14, Albacete, Spain.
Cellular and Tissue Therapies Branch, Division of Cellular and Gene Therapies, Center for Biologics and Research, U.S. Food and Drug Administration, Bethesda, MD 20892, USA.
Medical Staff, QEII Health Sciences Centre, Departments of Surgery and Medical Neuroscience, Dalhousie University, Halifax B3H 4R2, Canada.
Motor neurons, which relay neural commands to drive skeletal muscle movements, encompass types ranging from “slow” to “fast,” whose biophysical properties govern the timing, gradation, and amplitude of muscle force. Here we identify the noncanonical Notch ligand Delta-like homolog 1 (Dlk1) as a determinant of motor neuron functional diversification. Dlk1, expressed by ~30% of motor neurons, is necessary and sufficient to promote a fast biophysical signature in the mouse and chick. Dlk1 suppresses Notch signaling and activates expression of the K+ channel subunit Kcng4 to modulate delayed-rectifier currents. Dlk1 inactivation comprehensively shifts motor neurons toward slow biophysical and transcriptome signatures, while abolishing peak force outputs. Our findings provide insights into the development of motor neuron functional diversity and its contribution to the execution of movements.
Slow or fast motor neurons respectively synapse with type I muscle fibers responsible for fatigue-resistant low-force contractions or fatigable type IIb muscle fibers eliciting brief high-force outputs. The biophysical properties of these motor neuron types are exquisitely matched to the muscle fiber contractile properties. For instance, slow motor neurons, which possess low activation thresholds and long afterhyperpolarizations, can sustain long periods of low-frequency firing. Fast motor neurons, in contrast, are larger, exhibit high activation thresholds with shorter afterhyperpolarizations, and can fire in high-frequency bursts. Motor neurons with properties falling between these two extremes (which we call intermediate motor neurons) innervate muscle fibers with similarly intermediate characteristics. We identified molecular markers for these motor neuron types and studied how motor neuron functional diversity is established.
We exploited the distinct fiber type composition of soleus, tibialis anterior, and quadriceps muscles in the early postnatal mouse hindlimb to retrogradely label, isolate, and obtain transcriptome profiles of motor pools enriched in motor neurons developing into either slow/intermediate or fast types. One of the genes associated with a fast motor pool profile encoded Dlk1, a type I transmembrane protein related to the Notch ligand Delta, which functions in adipogenesis, postnatal myogenesis, and adult neurogenesis. Dlk1 was selectively expressed by large α motor neurons, but not smaller α motor neurons or γ motor neurons, throughout the spinal cord. Moreover, motor pools innervating predominantly fast or slow/intermediate muscles respectively exhibited either high or low proportions of Dlk1+ motor neurons, together indicating selective expression of Dlk1 by fast motor neurons
Here we have shown that Dlk1 is both necessary and sufficient for determining fast motor neurons and their corresponding biophysical signature in the mouse and chick. Dlk1 implements expression of motor neuron type–specific genes such as Kcng4, which modulates a subset of neural activity parameters. The result is a biophysical signature in motor neurons that supports peak neuromuscular outputs. The strategy by which expression of a neural activity modulator is confined to a subset of neurons may similarly drive functional diversity elsewhere in the developing nervous system.
The overall lack of topographic organization for slow or fast motor neurons suggests that motor neuron type is acquired independently of the mechanisms that, before muscle innervation, determine motor neuron positional (column or pool) identities. We still do not know when subsets of motor neurons acquire type-specific biophysical signatures, to what extent motor neuron functional diversification involves signals from muscle, how motor neuron and muscle fiber types are matched, or what causes the differential vulnerability of motor neuron types to disease or aging. However, 57 years after the characterization of fast and slow motor neurons, we can now have insight into the molecular mechanisms that control their development and function.
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