1. PANTEAMIENTO DEL PROBLEMA
2.4 APRENDIZAJE CON INTELIGENCIAS MÚLTIPLES
The mechanisms we have described for controlling the genesis of neurons of sensory bristles operate also, with variations, in the genesis of virtually all other neurons—not only in insects, but also in other phyla. Thus in the embryonic central nervous system, both in flies and in vertebrates, neurons are generated from regions of expression of proneural genes akin to Achaete and Scute. The nascent neurons express Delta and inhibit their immediate neighbors, which express Notch, from becoming committed to neural differentiation at the same time. When Notch signaling is blocked, inhibition fails, and in the proneural regions neurons are generated in huge excess at the expense of non-neuronal cells (Figure 22–65).
In the central nervous system, however, an additional mechanism comes into play to help generate the very large numbers of neurons and glial cells that are needed: a special class of cells become committed as neural precursors, but instead of differentiating directly as neurons or glial cells, these undergo a long series of asymmetric divisions through which a succession of additional neu- rons and glial cells are added to the population. The mechanism is best under- stood in Drosophila, although there are many hints that something similar occurs also in vertebrate neurogenesis.
Figure 22–62Numb biases lateral inhibition during bristle development. At
each division of the progeny of the sensory mother cell, Numb protein is asymmetrically localized, producing daughter cells that differ. Note that some of the divisions are oriented with the mitotic spindle in the plane of the epithelium, others at right angles to it; the localization of Numb is controlled in different ways at these different types of division but plays a critical role at each of them in deciding cell fate. (Based on data from M. Gho, Y. Bellaiche and F. Schweisguth, Development
126:3573–3584, 1999. With permission from The Company of Biologists.)
300 mm Figure 22–63Planar cell polarity manifest in bristle polarity on a fly’s
back: the bristles all point backwards. (Scanning electron micrograph
courtesy of S. Oldham and E. Hafen, from E. Spana and N. Perrimon, Trends Genet. 15:301–302, 1999. With permission from Elsevier.)
In the embryonic central nervous system of Drosophila, the nerve-cell pre- cursors, or neuroblasts, are initially singled out from the neurogenic ectoderm by a typical lateral-inhibition mechanism that depends on Notch. Each neuro- blast then divides repeatedly in an asymmetric fashion (Figure 22–66A). At each division, one daughter remains as a neuroblast, while the other, which is much smaller, becomes specialized as a ganglion mother cell, or GMC. The ganglion mother cell will divide only once, giving a pair of neurons, or a neuron plus a glial cell, or a pair of glial cells. The neuroblast becomes smaller at each division, as it parcels out its substance into one ganglion mother cell after another. Even- tually, typically after about 12 cycles, the process halts, presumably because the neuroblast becomes too small to pass the cell-size checkpoint in the cell division cycle. Later, in the larva, neuroblast divisions resume, and now they are accom- panied by cell growth, permitting the process to continue indefinitely, generat- ing the much larger numbers of neurons and glial cells required in the adult fly. The larval neuroblasts, therefore, are stem cells: while not terminally differ- entiated themselves, they behave as a self-renewing and potentially inex- haustible source of terminally differentiated cells. In Chapter 23, where we dis- cuss stem cells in detail, we shall see that stem cells do not necessarily have to divide asymmetrically; but asymmetric division is one possible strategy, and the neuroblasts of the fly provide a beautiful example.
DIX PDZ DEP Wnt, or other ligand Frizzled activated Dishevelled protein Rho JNK cascade actin cytoskeleton b-catenin GSK3b, Axin, APC TCF GENE TRANSCRIPTION PLANAR CELL POLARITY (A) (B) apico-basal polarity
planar cell polarity
neural plate neurons
overproduced on injected side
inject truncated-Delta mRNA into one cell
at the 2-cell stage
fix and stain for neurons at neural
plate stage
0.2 mm
Figure 22–64The control of planar cell polarity. (A) The two branches of the
Wnt/Frizzled signaling pathway. The main branch, discussed in Chapter 15, controls gene expression via b-catenin; the planar-polarity branch controls the actin cytoskeleton via Rho GTPases. Different domains of the Dishevelled protein are responsible for the two effects. It is not yet clear which member of the Wnt signal protein family, if any, is responsible for activating the planar polarity function of Frizzled in Drosophila. (B) Cartoon of cells displaying planar polarity. In at least some systems, planar cell polarity is associated with asymmetric localization of the receptor Frizzled itself to one side of each cell. (See also Chapter 19, Figure 19–32.)
Figure 22–65Effects of blocking Notch signaling in a Xenopus embryo. In the
experiment shown, mRNA coding for a truncated form of the Notch ligand Delta is injected, together with LacZ mRNA as a marker, into one cell of an embryo at the two-cell stage. The truncated Delta protein produced from the mRNA blocks Notch signaling in the cells descended from the cell that received the injection. These cells lie on the left side of the embryo and are identifiable because they contain LacZ protein (blue stain) as well as the truncated Delta protein. The right side of the embryo is unaffected and serves as a control. The embryo is fixed and stained at a stage when the central nervous system has not yet rolled up to form a neural tube, but is still a more or less flat plate of cells—the neural plate— exposed on the surface of the embryo. The first neurons (stained purple in the photograph) have already begun to differentiate in elongated bands (proneural regions) on each side of the midline. On the control (right) side, they are a scattered subset of the proneural cell population. On the Notch-blocked (left) side, virtually all the cells in the proneural regions have differentiated as neurons, creating a densely stained band of neurons without intervening cells. Injections of mRNA coding for normal, functional Delta have an opposite effect, reducing the number of cells that differentiate as neurons. (Photograph from A. Chitnis et al., Nature 375:761–766, 1995. With permission from Macmillan Publishers Ltd.)