Fig. 8. Mitogen gradient model of how growth is patterned across the DV axis of spinal cord to determine its size and shape. (a) At the cellular level, Wnt1 and Wnt3a act as mitogens on neural precursors through the ß-catenin pathway to promote cell cycle progression and inhibit cell cycle exit. (b) Diagram of cross section of the developing spinal cord. Mitotically active neural precursors comprise the medially located ventricular zone. Neural precursors exit the cell cycle and differentiate to form laterally located neurons. The mitogens Wnt1 and Wnt3a are expressed in the dorsal midline and form a dorsal to ventral concentration gradient across the field of neural precursors. (c) The potential size and shape of the mitogen gradient defines the potential rates of proliferation and differentiation across the DV axis. The proliferation and differentiation rate gradients level off dorsally because mitogenic Wnts are saturating at dorsal levels. The net effects of proliferation and differentiation form a gradient termed ‘growth potential’ (d). The proliferation rate gradient and the differentiation rate gradient cross about midway along the DV axis in this diagram. At this crossing point, the proliferation rate is equal to the differentiation rate meaning the population of precursors should be steady in number. Dorsal to this point the number of precursors is continually increasing, and ventral to this point the number of precursors is continually decreasing. The ventral extent of the growth potential gradient corresponds to the point at which the area between the curves above the crossing point equals the area between the curves below the crossing point such that the field of cells should not grow any further ventrally. (e) Different stages of the development of the spinal cord showing how it ‘grows into’ the size and shape specified by the growth potential gradient. The neural tube is initially small and round in cross section. At this early stage, Wnt1 and Wnt3a can diffuse across the entire DV axis to cause high rates of proliferation and low rates of differentiation across the entire DV axis. These high rates of proliferation and low rates of differentiation cause the neural tube to expand. As the neural tube expands, Wnt1 and Wnt3a become limiting at ventral levels causing higher rates of differentiation and lower rates of proliferation at ventral levels. This difference in growth potential across the DV axis causes the neural tube to become asymmetric; the ventricular zone becomes thicker dorsally than it is ventrally, and the mantle zone becomes thicker ventrally than it is dorsally. The neural tube continues to grow across its DV axis until it reaches a limit defined by the growth potential. Once this limit in DV size is reached, the developing spinal cord only grows across the medial-lateral and anterior-posterior axes by adding more neurons to the mantle zone. The arrows show the treadmilling movement of neural precursors ventrally away from the growth organizer caused by proliferation and the movement of precursors laterally to form neurons as they differentiate.