Hox gain of function Hox loss of function family of transcription regulators that we encountered in Chapter 7. These proteins drive cells to differentiate into muscle, expressing muscle-specific actins and myosins and all the other specialized cytoskeletal, metabolic, and membrane proteins that a muscle cell needs. Analogously, members of the Achaete/Scute family of transcription regulators drive cells to become neural progenitors. In both these examples, the proteins belong to the basic helix–loop–helix (bHLH) class of transcription regulators (see p. 377), and the same is true for many of the other proteins that induce the differentiation of particular cell types. These master transcription regulators exert their powerful differentiation-inducing activity by binding to many different regulatory sites in the genome and thereby controlling the expression of large numbers of downstream target genes. In one well-studied case, that of an Achaete/Scute family member called Atonal homolog 1 (Atoh1), the number of direct target genes in the mouse genome is more than 600. It is important to note, however, that even such powerful drivers of cell differentiation can have radically different effects according to the context and history of the cells in which they act: Atoh1, for example, drives differentiation of certain classes of neurons in the brain, of sensory hair cells in the inner ear, and of secretory cells in the lining of the gut.
Other genes encoding transcription regulators can drive the formation and assembly of the multiple cell types that constitute an entire organ. A famous example is the transcription regulator Eyeless. When it is artificially expressed in a patch of cells in the leg precursors of Drosophila, a well-organized eye-like organ develops on the leg, with the various eye cell types correctly arranged (see Figure 7–35B); conversely, loss of the Eyeless gene results in flies that lack eyes. Moreover, loss of the Eyeless homolog Pax6 in vertebrates likewise leads to loss of eye structures. Similar organ-selector proteins are known for foregut, heart, pancreas, and other organs. They are all master transcription regulators that directly regulate hundreds of target genes, the products of which then specify and construct the different elements of the appropriate organ. However, as in the example of Atoh1, they usually exert their specific effect only in combination with the right partners, which are only expressed in cells that were appropriately primed during their earlier development.
After the establishment of the basic body plan and the generation of organ precursors, many further steps of pattern refinement are required to achieve the adult pattern of terminally differentiated cells in tissues and organs. As we discussed
Figure 21–33 Control of anteroposterior pattern by Hox genes in the mouse.
(a,B) a normal mouse (wild type) has about 65 vertebrae, differing in structure according to their position along the body axis: 7 cervical (neck), 13 thoracic (with ribs), 6 lumbar [bracketed by yellow asterisks in (B)], 4 sacral [bracketed by red asterisks in (B)], and about 35 caudal (tail).
shows a side view and (B) shows a dorsal view; for clarity, the limbs have been removed in each picture.
the HoxA10 gene is normally expressed in the lumbar region (together with its paralogs HoxC10 and HoxD10); here it has been artificially expressed in the developing vertebral tissue all along the body axis. as a result, the cervical and thoracic vertebrae are all converted to a lumbar character. (D) conversely, when HoxA10 is removed along with HoxC10 and HoxD10, vertebrae that should normally have a lumbar or sacral character take on a thoracic character instead. (a and c, from M. carapuço et al., Genes Dev. 19:2116–2121, 2005. With permission from cold Spring harbor Laboratory  press; B and D, from D.M. Wellik and