Key Points
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Development of more than 1,000 distinct neuronal subtypes in the mammalian central nervous system is governed by distinct genetic codes. The vertebrate hindbrain provides an attractive model for understanding these neuronal codes. The cranial motor nerves and sensory ganglia are formed in a stereotypical manner, and each has a unique appearance and targets specific tissues.
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In the adult brainstem, the anatomical organization of the cranial nerves reflects their embryonic origins. The three motor neuron subtypes and the components of the sensory ganglia can be characterized by the positions of their cell bodies, axonal trajectories and gene expression patterns.
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Patterning of the hindbrain and cranial nerves occurs sequentially. Initially, cells are compartmentalized along the anteroposterior axis into seven or eight segments, known as rhombomeres. These provide anteroposterior positional information, and cell–cell interactions and dorsoventral signals within each rhombomere promote neuronal differentiation.
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Genes involved in early hindbrain patterning, particularly those required for the establishment and maintenance of rhombomeres, are essential for the formation of cranial nerves. In 1964, Deol described abnormal hindbrain segmentation and cranial nerve defects caused by the mouse kreisler mutation. Our understanding of the genetic requirements for rhombomere and early cranial nerve development was advanced by the discovery that Hox gene expression respects rhombomere boundaries, and by the advent of targeted mutagenesis.
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The anteroposterior information provided by rhombomeres is integrated with dorsoventral positional signals provided by sonic hedgehog, which is emitted by the ventrally located floorplate, and signals from the dorsal roofplate.
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Variations in Hox gene levels might reflect and be involved in the integration of anteroposterior and dorsoventral positional values. Each Hox gene might show not only a unique rhombomere-specific expression pattern, but might also be expressed in a specific neuronal class.
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Do neural determinants induced along the dorsoventral axis act in subtype-specific programmes or in general neuronal differentiation programs? Inactivation or ectopic expression of factors such as Nkx2.2, Pax6, Lhx2 and Lhx4 causes fate switches, suggesting that they act in subtype-specific differentiation. Analyses of Lim homeodomain proteins support the concept of a subtype-specific code, in this case to define early motor neuron identity.
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As neuronal cell bodies migrate to their final resting site and undergo maturation, some determinants are expressed transiently or in response to environmental signals. The dynamic interpretation of location-specific information is illustrated by mouse mutations that affect development of the facial branchiomotor nucleus.
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The molecular mechanisms underlying the specification of sensory, sympathetic and parasympathetic neuronal subtypes in the cranial ganglia are beginning to be elucidated.
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In addition to the neurons that comprise the cranial motor nerves, the hindbrain gives rise to a complex neuronal circuitry that governs rhythmic activities, such as breathing. This is known as the central respiratory centre.
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5-Hydroxytryptamine (5-HT, serotonin)-containing neurons coordinate an animal's assessment of its internal and emotional state, and its response to its environment. Most of these neurons are born in two clusters in the ventral portion of the hindbrain, and are later organized into the nine raphe nuclei.
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As hindbrain neurons mature, their axons initially extend towards their target by repulsion from specific rhombomeres and attraction towards the dorsal or ventral neural tube. The axons home in on their final destination by responding to highly specific cocktails of attractants, repellents and survival factors.
Abstract
Over the past decade, we have begun to understand the molecular genetics of cranial nerve development through the analysis of mouse mutants. Nerve identity is imparted by genes involved in anteroposterior patterning, such as the Hox genes, kreisler and Krox20. Neuronal determinants, including Lim homeobox genes, dictate neuronal subtype along the dorsoventral axis. Subsequent neuronal differentiation, and cell body and axon migration, is governed by subtype-specific gene expression, which is transient at times. So far, only a few cranial-axon-specific guidance molecules have been identified. The insights from these genetic analyses will help to guide future analyses of cranial nerve development in vertebrates.
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Acknowledgements
Due to space limitations, I was able to include only a fraction of pertinent references in table 1. I apologize to those whose work could not be acknowledged here.
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Glossary
- MOEBIUS SYNDROME
-
A disorder characterized by facial paralysis, attributed to defects in development of the sixth and seventh cranial nerves.
- PARAXIAL MESODERM
-
A region of the mesoderm adjacent to the notochord, which becomes segmented rostrocaudally to give rise to the somites early in development.
- PRECHORDAL MESODERM
-
A tissue derived from the node, lying at the rostral tip of the head process (notochord).
- PLACODES
-
Ectodermal thickenings that give rise to sensory structures or ganglia.
- LEUCINE ZIPPER
-
A leucine-rich domain within a protein that binds to other proteins with a similar domain.
- HOMEOBOX
-
A sequence of about 180 base pairs that encodes a DNA-binding protein sequence known as the homeodomain.
- PAIRED BOX
-
A homeodomain that is homologous to the DNA-binding domain of the Drosophila gene paired.
- ZINC FINGER
-
A protein module in which cysteine or cysteine–histidine residues coordinate a zinc ion. Zinc fingers are often used in DNA recognition and in protein–protein interactions.
- BASIC HELIX–LOOP–HELIX
-
A structural motif present in many transcription factors, which is characterized by two α-helices separated by a loop. The helices mediate dimerization, and the adjacent basic region is required for DNA binding.
- ETHYLNITROSOUREA
-
An alkylating agent that is the most powerful compound available for mutagenesis in the mouse. It predominantly produces point muations or small lesions in the DNA.
- GENE-TRAP SCREEN
-
A mutation strategy that makes use of insertion vectors to trap or isolate transcripts from flanking genes. The inserted sequence acts as a tag from which to clone the mutated gene.
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Cordes, S. Molecular genetics of cranial nerve development in mouse. Nat Rev Neurosci 2, 611–623 (2001). https://doi.org/10.1038/35090039
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DOI: https://doi.org/10.1038/35090039
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