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THE NEURAL TUBE AND NEURAL CREST
THE GENES WHICH CAUSE THE DEVELOPMENT OF NEURONS
What genes allow cells to differentiate into neurons? What genes guide the early development of the nervous system? There are many, only a few of which are given here.
Of 116 genes known to be involved in the development of the brain and nervous system of flatworms, more than 95% were shared with higher bilateran animals such as nematodes, flies, and humans. Homologs of all 116 existed in humans. Homologs of about a third of these genes existed in organisms which lack a nervous system, such as yeast (Mineta, 2003).
These shared genes included FGF, noggin, frizzled (a Wnt receptor), immunoglobulin/cadherin family members, otx, neuropeptide Y, NCAM, BMP receptors, and rhodopsin (Mineta, 2003). Members of the Wnt gene family are involved in the formation of the vertebrate brain and also in the regeneration of planarian brain (Marshal, 2003). apterous is a member of the LIM-homeodomain family which possesses 2 zinc finger-like domains in addition to its homeodomain. Both apterous and mammalian homologs are expressed in nerve cords, eyes, brains, limbs, and olfactory structures. The human gene can replace the activity of apterous in the body of the fly (Rincon-Limas, 1999).
There is a new family of genes (C. elegans unc-76) known to affect axonal growth in nematodes and humans. Mutations affect the formation of fascicles and nerve cords (Bloom, 1997). Tunicates possess genes involved in the induction of neural tissue and for neural function which link them to vertebrates rather than protostomes (such as a greater diversity of Bmp and Wnt signals, the gene Nodal, SCO-spondin, noelin, and rhodopsin photoreceptors related to deep brain/pineal opsins of vertebrates) (Dehal, 2002). Mutation of the nou-darake (Djndk) gene in planarians caused an ectopic brain to form in the trunk region (Mineta, 2003).
As brains became more complex, additional
proteins were recruited to achieve this complexity. A significant feature of the mammalian cerebrum
is its organization into layers. The
protein reelin is involved in a number of neural
functions in amniotes such as neuronal migration to form layered regions
of the cerebral cortex, synapse formation in the hippocampus, and axonal
is also expressed throughout the lamprey brain (Perez-Costas,
2002). Although there have been
observations of molecular differences between human and chimp brains,
many correspond to varying level of a protein’s expression rather than
the existence of new proteins. There
are a large number of genes which are more highly expressed in the brains
of humans than those of other primates (
In embryonic development, the formation of a distinct organizer region is the first step in the development of the nervous system. The organizer region of dorsal mesoderm forms the midline mesoderm of the notochord and produces the signals for the induction of the nervous system. All vertebrates require HNF3β for the formation of the organizer. In frogs, there are 5 signals for neural induction made in this organizer region: noggin, follistatin, chordin, xnr, and cerebrus (Harland, 2000). Noggin, chordin, cerebrus and follistatin bind to bone morphogenetic proteins (BMPs); the first two do so with high affinity and prevent BMPs from binding hteir receptors. Lefty and Activin may be receptor antagonists for Nodal (Harland, 2000).
The postanal tail of chordates was a novel structure which evolved long after ancestral organisms had developed mechanisms for the induction of neural tissue. It is perhaps not surprising, then, that neural tissue in the tail develops in a way which differs from that of the cranial portion of chordates. In vertebrates, the caudal end of the embryo does not develop neural tissue in the same manner as the cranial portion. The tail develops neural tissue, muscle, bone, blood vessels from tailbud mesenchyme without ever dividing into three germ layers. This secondary neurulation in vertebrates is distinct from the primary neurulation through which the anterior end develops. Ectoderm and endoderm are primary germ layers which induce the two secondary germ layers, mesoderm and neural crest cells (Hall, 1999).
THE NEURAL CREST
A unique group of important embryonic cells called neural crest cells were a vertebrate innovation. Neural crest cells develop into a number of cell types including sensory neurons, adrenergic neurons, cholinergic neurons, Rohon-Beard cells, satellite cells, and glial cells. As a result, the neural crest contributes to spinal ganglia, the sympathetic and parasympathetic divisions of the ANS, and brain, among other structures (Hall, 1999). In tunicates, there is evidence of a protoneural crest in the pigmented cells along the neural tube (Hall, 1999). Although there are no neural crest cells in tunicates, the expression of the snail gene family member, Hrsna, indicates that some of the characteristics of neural crest cells may be present. (Meinertzhagen, 2001). While Amphioxus lacks neural crest cells, it expresses many of the important genes involved in the differentiation of vertebrate neural crest cells in the region of the junction between the neural plate and the non-neural ectoderm. Vertebrate neural crest cells employed genes which were already present in vertebrate ancestors (Ahlberg, 20-5).
Neural crest induction involves genes such as BMP, chordin, FGF, TGF (at Hensen’s node), WNT, Shh, dorsalin, odd-paired (a Drosophila pair rule gene), and the snail zinc finger gene. Many of these genes perform other functions as well and are known (or, at least, members of their gene families are known), in more primitive animals which lack neural crest cells.
Neural crest cells develop into a number of cell types including sensory neurons, adrenergic neurons, cholinergic neurons, Rohon-Beard cells, satellite cells, glial cells, chromaffin cells, parafollicular cells, calcitonin-producing cells, melanocytes, chondroblasts, osteoblasts, odontoblasts, fibroblasts, cardiac mesenchyme, striated myoblasts, smooth myoblasts, mesenchymal cells, adipocytes, angioblasts and the sensory ganglia of the 5th, 7th, 9th, and 10th cranial nerves (Moore, p. 72; Hall, 1999, p. 15). As a result, the neural crest contributes to spinal ganglia, the sympathetic and parasympathetic divisions of the ANS, the thyroid gland, ultimobranchial body, adrenal gland, craniofacial skeleton, teeth, connective tissue, adipose, cardiac septa, dermis, eye, cornea, endothelia, blood vessels, heart, dorsal fin, and brain (Hall, 1999). Post-otic neural crest (PONC) cells contribute to shoulder and neck structures, as do cells derived from mesoderm. The trapezius and coracobranchial muscles which open and retract the jaw are derived from neural crest cells (Matsuoka, 2005). The larynx is derived from neural crest cells while the trachea is derived from mesoderm (Matsuoka, 2005).
Ectoderm and endoderm are the primary embryonic germ layers which induce the two secondary germ layers, mesoderm and neural crest cells. Given the diverse structures made by neural crest cells, some consider it to be a fourth germ layer of the embryo, in addition to ectoderm, endoderm, and mesoderm. Ernst Haeckel first used the terms ectoderm, endoderm, and mesoderm in 1874. The germ theory of development (with the conclusion that cartilage and mesenchyme were derived from mesoderm) was so entrenched that there was resistance to the discoveries that these structures could be derived from the neural crest in the 1950s (Hall, 1999). Vertebrate skeletal tissues have a dual nature, since they are formed by the mesoderm in the trunk and limbs and by neural crest cells in the head. These two skeletons have different embryonic and evolutionary origins. Neural crest cells of the skull can form bone, dentine, and enamel but not cartilage (Hall, 1995). Mice with null mutations of Sox9 did not develop cartilaginous structures (such as pharyngeal arches and the nasal apparatus) which are formed by cranial neural crest cells (Mori-Akiyama, 2003).
Neural crest cells were a vertebrate innovation.
Amphioxus lacks them and lampreys have them (the situation in hagfish
is not yet clear). Although Amphioxus lacks neural crest cells, it
expresses many of the important genes involved in the differentiation
of vertebrate neural crest cells in the region joining the neural plate
and the non-neural ectoderm (Ahlberg, 20-5). In Amphioxus,
the expression of Pax3/7, Msx, Dll,
and Snail genes suggest the presence of a proto-neural crest (
Craniates possess placodes which form in or next to the neural crest boundary although their relationship to the crest is not yet clear. They form the nose, ear, and central ganglia of cranial nerves (Hall, 1999).
Neural crest cells from the area of the mid-otic placode and the third somite migrate to the heart and great vessels. Loss of these cells results in abnormailites of the heart such as a double aortic arch which encircles the trachea, a persistent truncus arteriosus, and a persistence of the right dorsal aorta (Stoller, 2005).