Patterning, specification, and differentiation in the developing hypothalamus

Abstract

Owing to its complex structure and highly diverse cell populations, the study of hypothalamic development has historically lagged behind that of other brain regions. However, in recent years, a greatly expanded understanding of hypothalamic gene expression during development has opened up new avenues of investigation. In this review, we synthesize existing work to present a holistic picture of hypothalamic development from early induction and patterning through nuclear specification and differentiation, with a particular emphasis on determination of cell fate. We will also touch on special topics in the field including the prosomere model, adult neurogenesis, and integration of migratory cells originating outside the hypothalamic neuroepithelium, and how these topics relate to our broader theme.

FIGURE 1

Schematic showing the inductive signals that act on the ventral neural plate. The posterior neural plate receives inductive signals from the notochord to become floor plate, whereas the more anterior neural plate that goes on to become the hypothalamus receives a different set of inductive signals from the prechordal plate. Circles represent signaling from the prechordal plate/notochord, whereas the diagonal bars in the neural plate represent local gene expression. It should be noted that the juxtaposition of the prechordal plate and the hypothalamic neural plate is transient. These structures migrate out of register with each other. The prechordal plate reaches its final rostral position in advance of the hypothalamic neural plate, which migrates over and rostrally past the prechordal plate. Thus by the time the floor plate and the hypothalamic neural plate are specified, the prechordal plate actually resides caudal to the hypothalamic neural plate. A, anterior; P, posterior

FIGURE 2

Sagittal view of morphogen expression over the course of development in the mouse forebrain, emphasizing the hypothalamus. (a–c). Forebrain Shh expression from E8.5 through E11.5. (d). Hypothalamic Shh expression at E12.5. White bars represent areas of diffuse Shh expression. (e) Wnt expression in the forebrain at E9.5. (f). Wnt expression in the hypothalamus at E12.5. Wnt 7a/7b is expressed in interneuron progenitors only while Wnt 3/3a and Wnt 8a/8b are expressed more broadly. BP, basal plate; ZLI, zona limitans intrathalamica; POA, preoptic area; Tel, telencephalon; PrTh, prethalamus; Hy, hypothalamus.

FIGURE 3

Sagittal map of nuclei in the mouse hypothalamus at E12.5 at the level of the third ventricle. ZLI, zona limitans intrathalamica; PreThal, prethalamus; EmThal, thalamic eminence; PVN, paraventricular nucleus; vAH, ventral anterior hypothalamus; ant. ID, anterior intrahypothalamic diagonal; ID, intrahypothalamic diagonal; ARC, arcuate nucleus; VMH, ventromedial hypothalamus; PMN, premammillary nucleus; TT, tuberomammillary terminal; MMN, mammillary nucleus; SMN, supramammillary nucleus.

FIGURE 4

(a–d) Coronal diagrams of the nuclei of the developing hypothalamus at ~E15.5. Insets in the upper right-hand corners indicate the approximate position of these coronal sections in the sagittal plane. Note that the angle of the cut shown in the developing hypothalamus sometimes places nuclei normally present on different coronal planes in typical adult brain sections on the same plane in our diagram (e.g.: SCN and DMH in panel b). Abbreviations indicating divisions of the hypothalamus larger than single nuclei as described in the text (e.g.: AH and PH) here show the disposition of poorly defined and/or less well-studied nuclei within those regions. For example, though the PVN and SCN are derived from the broader AH, in this figure they are shown separately and the region labeled AH only encompasses less-studied regions we do not discuss in detail, such as the periventricular, subparaventricular, and retrochiasmatic nuclei. SCN, suprachiasmatic nucleus; DMH, dorsomedial hypothalamic; PVN, paraventricular nucleus; AH, anterior hypothalamus; PH, posterior hypothalamus.

FIGURE 5

Factors controlling specification and differentiation within specific nuclei or regions of the developing hypothalamus. Regions depicted include the dlAH (a), SCN (b), DMH (c), VMH (d), ARC (e), and PH (f). Blue arrows indicate factors that direct cells within the region toward the fate pointed at by its arrowhead, whereas red arrows indicate factors that inhibit the indicated fate. Serial arrows show that the downstream arrow is dependent upon the upstream arrow for its expression, directly or indirectly. Parallel arrows represent factors that act in concert to direct cells toward a common fate, but are not known to be directly dependent on one another for their expression. dlAH, dorsolateral anterior hypothalamus; SCN, suprachiasmatic nucleus; DMH, dorsomedial hypothalamic; VMH, ventromedial hypothalamus; ARC, arcuate nucleus; PH, posterior hypothalamus.