Patterning the developing diencephalon

Abstract

The diencephalon is the embryonic precursor to the caudal forebrain. The major diencephalic derivative is the thalamus, which functions as a relay station between the cortex and lower nervous system structures. Although the diencephalon has been recognized as a vital brain region, our understanding of its development remains superficial. In this review, we discuss recent progresses in understanding one essential aspect of diencephalic development, diencephalic patterning. Signaling centers identified in the zona limitans intrathalamica and along the dorsal and ventral midlines have emerged as essential organizers in diencephalic patterning. The cumulative data reveal that the diencephalon shares some developmental principles with more caudal brain regions, whereas other mechanisms are unique to this region.

Introduction

In vertebrates, the anterior neural epithelium undergoes morphological subdivisions to generate vesicle-like structures known as the prosencephalon (forebrain), mesencephalon (midbrain), and rhombencephalon (hindbrain). The prosencephalon becomes further divided into the telencephalon and diencephalon. The telencephalon gives rise to the cerebral cortex, basal ganglia, and hippocampus, whereas the diencephalon develops into the thalamus, epithalamus, and pretectum in the mature brain (the status of the hypothalamus as a part of the diencephalon structure remains controversial). Thus, the telencephalon and diencephalon are the embryonic anlagen of higher cognition and integration centers in the brain. Although these two regions of the forebrain are functionally linked, their structural organization is distinct. For example, in mammals, the thalamus (the major diencephalic derivative) consists of clusters of neurons organized into nuclei, which are morphological and functional units, whereas the cerebral cortex (telencephalic derivative) is a laminar sheet of neurons where each layer serves specific function. Therefore, one can presume that distinct developmental strategies must be utilized by these two brain regions. Although many studies have focused on molecular regulation of telencephalic development (for reviews, see Campbell, 2003, Grove and Fukuchi-Shimogori, 2003, Rallu et al., 2002, Rubenstein et al., 1998, Schuurmans and Guillemot, 2002), relatively few studies have addressed development of the diencephalon.

The key feature of diencephalic development is the formation of nuclei along the anterior–posterior (AP) and dorsal–ventral (DV) axes. In the diencephalon, neural progenitor cells undergo proliferation in the ventricular zone of the third ventricle. Once they exit the cell cycle, post mitotic cells migrate to the mantle zone and they aggregate into various clusters called nuclei. Differentiated neurons in each nucleus have distinct morphologies, employ specific neural transmitters, and generate neural connection to different regions of the brain (Jones et al., 1997). In order to build accurate neural circuits, it is essential to form each nucleus in the correct location and at the appropriate time in development. Based on birthdating studies in mammals, it has been hypothesized that the progenitor cells in the ventricular zone (the germinal epithelium) are organized as mosaic patches, each giving rise to neurons in specific nuclei of the diencephalon (Altman and Bayer, 1988). As a result, it was assumed that the initial requirement for the accurate allocation of each nucleus is the precise establishment of AP and DV identities in the neural progenitor cells. Studies from the spinal cord suggest that the progenitor cells acquire their regional identities through transcription factor expression codes, which are regulated by secreted signaling molecules such as Shh (Jessell, 2000). Although it has not been studied as thoroughly, a similar mechanism has been suggested in the diencephalon (Hashimoto-Torii et al., 2003).

The diencephalic derivatives, and the thalamic nuclei in particular, have intricate connections with functional areas in the cortex (Jones et al., 1997). For instance, sensory relay nuclei in the thalamus – including ventrobasal, lateral geniculate, and medial geniculate nuclei – send projections specifically to somatosensory, visual, and auditory cortices, respectively (Fig. 1) (Jones et al., 1997, Lopez-Bendito and Molnar, 2003). Furthermore, the thalamocortical projections play essential roles in shaping cortical area development (Kaas et al., 1999, Pallas, 2001). Although clearly important, the timing of this influence is controversial; thalamocortical projections do not appear to influence the initial cortical area specification but are necessary for proper differentiation of cortical areas (Cohen-Tannoudji et al., 1994, Kaas et al., 1999, Miyashita-Lin et al., 1999, Nakagawa et al., 1999, Nothias et al., 1998, Pallas, 2001). Therefore, considering its intimate relationship with the cortex as well as its function as an independent brain structure, understanding diencephalic development provides many insights into brain development.

In this review, we attempt to integrate the current data addressing the molecular mechanisms underlying diencephalic development to the existing studies on AP and DV patterning of the diencephalon. For AP patterning, several studies debating whether or not the diencephalon is a segmented structure will be discussed along with the formation and function of a diencephalic signaling center, the ZLI (zona limitans intrathalamica). Also, molecular patterning at the anterior and posterior boundaries of the diencephalon will be covered. For DV patterning, we will focus on the two signaling centers, the floor plate and roof plate, and the signaling molecules that they produce.