Specification of Neuronal Cell Types

The adult nervous system is characterized by a multitude of different neuron types that interact in complex neuronal circuits. The distinct neuronal subtypes are generated in a defined and invariant spatial and temporal order during development, and the ordered generation of neurons is a prerequisite for the establishment of the correct neuronal connectivity. We have concentrated in the last years on the characterization of neurons in the dorsal spinal cord and hindbrain, which receive and process sensory information from the periphery. These neurons are important for sensory perceptions, for instance for the sensation of pain or touch.

 

The sense of touch relies on detection of mechanical stimuli by specialized mechanosensory neurons. We could show that the transcription factor c-Maf/c-MAF is crucial for mechanosensory function in mice and humans. The development and function of several rapidly adapting mechanoreceptor types are disrupted in c-Maf mutant mice. In particular, Pacinian corpuscles, a type of mechanoreceptor specialized to detect high-frequency vibrations, are severely atrophied. In line with this, sensitivity to high-frequency vibration is reduced in humans carrying a dominant mutation in the c-MAF gene. Thus, our work identifies a key transcription factor specifying development and function of mechanoreceptors and their end organs (Wende 2012).

 


 

Pacinian corpuscles in c-Maf mutant mice. c-Maf mutation in mice causes a loss of Pacinian corpuscles and disrupts the morphologies of remaining corpuscles.

 

Myelination depends on the synthesis of large amounts of myelin transcripts and proteins, and is controlled by Nrg1/ErbB/Shp2 signaling. We developed a novel pulse labeling strategy based on SILAC to measure the dynamics of myelin protein production in mice. We found that protein synthesis is dampened in the maturing postnatal peripheral nervous system and myelination then slows down. Remarkably, sustained activation of MAPK signaling by expression of the Mek1DD allele in mice overcomes the signals that end myelination, resulting in continuous myelin growth. MAPK activation leads to minor changes in transcript levels but massively upregulates protein production. Previous work demonstrated that loss of ErbB3/Shp2 signaling impairs Schwann cell development and disrupts the myelination program on transcriptional and translational levels. We find that activated MAPK signaling strikingly compensates for the absence of ErbB3 or Shp2 during Schwann cell development and myelination and rescues translational and transcriptional deficits (Sheean 2014).

 


 

Expression of Mek1DD in Schwann cells compensates for the loss of Shp2 or ErbB3. Electron microscopy analysis at P15 of sciatic nerves of Egr2Cre;Shp2f/f, Egr2Cre;Shp2f/f;Mek1DD and control mice.

 

The protease Bace1 was identified through its critical role in production of amyloid-beta-peptides, the major component of amyloid plaques in Alzheimer's disease. Bace1 is considered a promising target for the treatment of this pathology, but processes additional substrates, among them Nrg1. Our biochemical analysis indicated that Bace1 processes the Ig-containing Nrg1 beta1 isoform. We find that a graded reduction in IgNrg1 signal strength in vivo results in increasingly severe deficits in formation and maturation of muscle spindles, a proprioceptive organ critical for muscle coordination. Further, we show that Bace1 is required for formation and maturation of the muscle spindle. Finally, pharmacological inhibition and conditional mutagenesis in adult animals demonstrate that Bace1 and Nrg1 are essential to sustain muscle spindles and to maintain motor coordination. Our results assign to Bace1 a role in the control of coordinated movement through its regulation of muscle spindle physiology, and implicate IgNrg1-dependent processing as a molecular mechanism (Cheret 2013).

 


 

Immunohistological analysis of muscle spindles from control and Bace1 mutant mice at P0. Intrafusal fibers express Egr3; the nascent capsule displays collagen IV staining; contacting sensory fibers are NF200+.