skip to main content
US FlagAn official website of the United States government
dot gov icon
Official websites use .gov
A .gov website belongs to an official government organization in the United States.
https lock icon
Secure .gov websites use HTTPS
A lock ( lock ) or https:// means you've safely connected to the .gov website. Share sensitive information only on official, secure websites.


Title: Changed Innervation Upon Loss of Mandibular Division of Trigeminal Nerve to Muscles of Mastication
INTRODUCTION:The gastrulation brain homeobox (Gbx) genes are essential for patterning and maintenance of neurons along the anteroposterior axis of the developing neural tube. Knockout (ko) of Gbx2 results in neonatal lethality associated with neurological and other defects. To understand pathologies, ko studies are not realistic as gene loss usually results in death before birth. Gbx2 neo/neo mutant mice express 6-10% of the wildtype Gbx2 expression levels. They have milder malformations than ko mice but lack the cerebellar vermis and mandibular division of the trigeminal nerve (3rd division of 5th cranial nerve = V3), among other defects. These Gbx2 neo/neo mutant mice die perinatally as they are unable to suckle due to lack of motor innervation via V3 to the muscles of mastication. Muscle cells develop largely without interaction with their motor nerve. However, the final differentiation of myocytes requires interactions with nerve fibers. Unexpectedly, the muscles of mastication appear normal in Gbx2 neo/neo mutant mice, despite the lack of V3. METHODS:We performed microdissections of neonate wildtype and Gbx2neo/neo mutant mice. Additionally, we embedded mutant and wildtype mouse embryos in paraffin, serial sectioned them (7 μm), stained the sections with Azan staining, and analyzed specimen microscopically. RESULTS:Current analysis of the data to identify where nerve fibers in the muscles of mastication originate is in process. We favor the origin of these fibers from the facial nerve (7th cranial nerve), which has several overlapping territories with the trigeminal nerve. CONCLUSIONS:Muscles require innervation for their final differentiation steps. The loss of a nerve can result in the invasion of another nerve into the territory of the lost one, which rescues muscle differentiation but not muscle function. IACUC Ziermann Med-20-02, Funding NSF #2000005 to Ziermann.  more » « less
Award ID(s):
2000005
PAR ID:
10616893
Author(s) / Creator(s):
;
Publisher / Repository:
Congress of Neurological Surgeons 2024
Date Published:
Journal Name:
Neurosurgery
Volume:
70
Issue:
Supplement_1
ISSN:
0148-396X
Page Range / eLocation ID:
138 to 138
Format(s):
Medium: X
Sponsoring Org:
National Science Foundation
More Like this
  1. A key player in brain and neural crest development is the gastrulation-brain-homeobox (Gbx) transcription factor family member, Gbx2. During the early stages of gastrulation, Gbx2 RNA is broadly expressed in the prospective hindbrain and posterior region of the embryo. Later it becomes restricted to a sharp transverse band at the interface between the prospective midbrain and hindbrain, and is maintained in the anterior hindbrain in the developing neuroaxis (Bouillet et al. 1995; Li & Joyner 2001; Martinez-Barbera et al. 2001). Gbx2 regulates diverse developmental processes, including anteroposterior patterning within the mid-/hindbrain boundary and anterior hindbrain (Burroughs-Garcia et al. 2011). Expression of Gbx2 is required for the correct formation of rhombomeres r1-r3 (Wassarman et al. 1997). Loss of Gbx2 function in mouse embryos (Gbx2-/-), results in aberrant neural crest cell patterning leading to defects in neural crest derivatives and to abnormalities in the central nervous system, craniofacial, and cardiovascular components (Byrd & Meyers 2005). Li et al. (2009) demonstrated that Gbx2 is a direct target of the neural crest inducer Wnt, and is essential for neural crest induction. Together, these studies show that Gbx2 resides upstream in the genetic cascade controlling neural crest development and directly regulates the expression of key molecules involved in the migration and survival of neural crest cells that differentiate into neural and other components (e.g., connective tissue) of the head and heart. It was shown that Gbx2neo/neo mouse embryos, in which wild-type levels of Gbx2 expression is reduced to 6-10% of normal, are useful to further elucidate the complexity concerning the role of Gbx2 in anterior hindbrain development (Waters & Lewandoski 2006). Among other malformations, in Gbx2neo/neo embryos the mandibular branch of the trigeminal nerve (CNV3) is absent. CNV3 innervates the muscles of mastication (e.g., pterygoids, masseter, temporalis). However these muscles are needed to suckle and neonate (P0) Gbx2neo/neo mice are not able to suckle and die perinatally (Langenbach & van Eijden 2001). Here we describe the anatomy of the trigeminal ganglion and the trigeminal nerves in neonate Gbx2neo/neo mice and evaluate if there are differences in the muscles of mastication in these mice as compared to wildtype specimens. We expected that we find clear abnormalities in the thickness of the masseter, temporalis, and other muscles innervated by CNV3. However, this is not the case, indicating that the innervation of a muscle is not, as previously thought, needed for the differentiation of the muscles. Histological analyses will give insights into the muscle cell structure and if this is altered in the Gbx2neo/neo mice, which could be related to the loss of motor innervation. The research was funded by NSF EiR HBUC 18-522 awarded to JMZ (#2000005) and STW (#1956450). Bouillet et al. (1995). Dev Dyn, 204: 372-82. Burroughs-Garcia et al. (2011). Dev Dyn, 240: 828-38. Byrd & Meyers (2005). Dev Biol, 284: 233-45. Langenbach & van Eijden(2001). Am Zool, 41: 1338-51. Li et al. (2009). Development, 136: 3267-78. Li & Joyner (2001). Development, 128: 4979-91. Martinez-Barbera et al. (2001). Development, 128: 4789-800. Wassarman et al. (1997). Development, 124: 2923-34. Waters & Lewandoski (2006) Development, 133: 1991-2000. Funding or Support Information: The research was funded by NSF EiR HBUC 18-522 awarded to JMZ (#2000005) and STW(#1956450). 
    more » « less
  2. Abstract Cranial nerves are key features of the nervous system and vertebrate body plan. However, little is known about the anatomical relationships and ontogeny of cranial nerves in crocodylians and other reptiles, hampering understanding of adaptations, evolution, and development of special senses, somatosensation, and motor control of cranial organs. Here we share three dimensional (3D) models an of the cranial nerves and cranial nerve targets of embryonic, juvenile, and adult American Alligators (Alligator mississippiensis) derived from iodine‐contrast CT imaging, for the first time, exploring anatomical patterns of cranial nerves across ontogeny. These data reveal the tradeoffs of using contrast‐enhanced CT data as well as patterns in growth and development of the alligator cranial nervous system. Though contrast‐enhanced CT scanning allows for reconstruction of numerous tissue types in a nondestructive manner, it is still limited by size and resolution. The position of alligator cranial nerves varies little with respect to other cranial structures yet grow at different rates as the skull elongates. These data constrain timing of trigeminal and sympathetic ganglion fusion and reveal morphometric differences in nerve size and path during growth. As demonstrated by these data, alligator cranial nerve morphology is useful in understanding patterns of neurological diversity and distribution, evolution of sensory and muscular innervation, and developmental homology of cranial regions, which in turn, lead to inferences of physiology and behavior. 
    more » « less
  3. AbstractMotor neurons are the longest neurons in the body, with axon terminals separated from the soma by as much as a meter. These terminals are largely autonomous with regard to their bioenergetic metabolism and must burn energy at a high rate to sustain muscle contraction. Here, through computer simulation and drawing on previously published empirical data, we determined that motor neuron terminals inDrosophila larvae experience highly volatile power demands. It might not be surprising then, that we discovered the mitochondria in the motor neuron terminals of bothDrosophila and mice to be heavily decorated with phosphagen kinases ‐ a key element in an energy storage and buffering system well‐characterized in fast‐twitch muscle fibres. Knockdown of arginine kinase 1 (ArgK1) inDrosophilalarval motor neurons led to several bioenergetic deficits, including mitochondrial matrix acidification and a faster decline in the cytosol ATP to ADP ratio during axon burst firing.image Key pointsNeurons commonly fire in bursts imposing highly volatile demands on the bioenergetic machinery that generates ATP.Using a computational approach, we built profiles of presynaptic power demand at the level of single action potentials, as well as the transition from rest to sustained activity.Phosphagen systems are known to buffer ATP levels in muscles and we demonstrate that phosphagen kinases, which support such phosphagen systems, also localize to mitochondria in motor nerve terminals of fruit flies and mice.By knocking down phosphagen kinases in fruit fly motor nerve terminals, and using fluorescent reporters of the ATP:ADP ratio, lactate, pH and Ca2+, we demonstrate a role for phosphagen kinases in stabilizing presynaptic ATP levels.These data indicate that the maintenance of phosphagen systems in motor neurons, and not just muscle, could be a beneficial initiative in sustaining musculoskeletal health and performance. 
    more » « less
  4. Myokines and exosomes, originating from skeletal muscle, are shown to play a significant role in maintaining brain homeostasis. While exercise has been reported to promote muscle secretion, little is known about the effects of neuronal innervation and activity on the yield and molecular composition of biologically active molecules from muscle. As neuromuscular diseases and disabilities associated with denervation impact muscle metabolism, we hypothesize that neuronal innervation and firing may play a pivotal role in regulating secretion activities of skeletal muscles. We examined this hypothesis using an engineered neuromuscular tissue model consisting of skeletal muscles innervated by motor neurons. The innervated muscles displayed elevated expression of mRNAs encoding neurotrophic myokines, such as interleukin-6, brain-derived neurotrophic factor, and FDNC5, as well as the mRNA of peroxisome-proliferator-activated receptor γ coactivator 1α, a key regulator of muscle metabolism. Upon glutamate stimulation, the innervated muscles secreted higher levels of irisin and exosomes containing more diverse neurotrophic microRNAs than neuron-free muscles. Consequently, biological factors secreted by innervated muscles enhanced branching, axonal transport, and, ultimately, spontaneous network activities of primary hippocampal neurons in vitro. Overall, these results reveal the importance of neuronal innervation in modulating muscle-derived factors that promote neuronal function and suggest that the engineered neuromuscular tissue model holds significant promise as a platform for producing neurotrophic molecules. 
    more » « less
  5. Background.Safe sensory-selective local anesthetics would be a major advance in the management of acute and chronic pain. Here we describe the sensory-selective local anesthetic properties and the toxicity profile of a known metabolite of amino-amide local anesthetics,2',6'-pipecolylxylidine (PPX). Methods.PPX was synthesized and made into its hydrochloride salt. PPX or ropivacaine (ROP) were injected at the sciatic nerve or intrathecally in rats, who then underwent modified hotplate (sensory) testing and weight-bearing (motor) testing. Rats injected with PPX or ROP were assessed for clinical toxicity endpoints. Conduction blockade was studied with single-unit recordings in mice. Biocompatibility was assessed histologically. Results.In male rats, sciatic sensory and motor block from 15 mM ROP lasted ~150 min; sensory nerve block from 30 mM PPX lasted 67.4 ± 17.4 min without motor block. Addition of chemical permeation enhancers to 30 mM PPX abolished sensory selectivity. Intrathecal 15 mM ROP produced sensory and motor block lasting ~15 min; sensory block from 30 mM PPX lasted 24.8 ± 8.7 min without motor block; repeated injection caused continuous sensory-selective block. In female rats, sciatic nerve blocks with ROP were similar to blocks in males, while blocks with PPX were sensory-selective but higher PPX concentrations were required. Ex vivo, 1.5 mM ROP caused reversible block of Aδ and C-fibers; 15 mM PPX blocked Aδ- but not C-fibers. Systemic 39.0 ± 1.8 mg/kg ROP caused severe clinical toxicity; 75.3 ± 3.2 mg/kg PPX caused none. Tissue reaction to PPX was benign, comparable to that of ROP. Conclusions.PPX provides sensory-selective local and neuraxial anesthesia with a good safety profile. The sensory selectivity may be attributable to the particular hydrophilic-hydrophobic balance of PPX. 
    more » « less