Molecular genetics of cranial nerve development in mouse

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. 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. 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. 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. 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. 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. 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. 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. The molecular mechanisms underlying the specification of sensory, sympathetic and parasympathetic neuronal subtypes in the cranial ganglia are beginning to be elucidated. 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. 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. 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.