Transcriptional Profile of the Developing Subthalamic Nucleus

Abstract

The subthalamic nucleus (STN) is a small, excitatory nucleus that regulates the output of basal ganglia motor circuits. The functions of the STN and its role in the pathophysiology of Parkinson's disease are now well established. However, some basic characteristics like the developmental origin and molecular phenotype of neuronal subpopulations are still being debated. The classical model of forebrain development attributed the origin of STN within the diencephalon. Recent studies of gene expression patterns exposed shortcomings of the classical model. To accommodate these findings, the prosomeric model was developed. In this concept, STN develops within the hypothalamic primordium, which is no longer a part of the diencephalic primordium. This concept is further supported by the expression patterns of many transcription factors. It is interesting to note that many transcription factors involved in the development of the STN are also involved in the pathogenesis of neurodevelopmental disorders. Thus, the study of neurodevelopmental disorders could provide us with valuable information on the roles of these transcription factors in the development and maintenance of STN phenotype. In this review, we summarize historical theories about the developmental origin of the STN and interpret the gene expression data within the prosomeric conceptual framework. Finally, we discuss the importance of neurodevelopmental disorders for the development of the STN and its potential role in the pathophysiology of neurodevelopmental disorders.

Keywords: basal ganglia; hypothalamus; prosomeric model; subthalamic nucleus; transcription factors.

Figure 1.

The prosomeric model of forebrain subdivision is based on gene expression patterns. The embryonic mouse brain can be divided in rhombencephalon–hindbrain (rhombomeres r1–r8), isthmus, mesencephalon, diencephalon (prosomeres p1–p3, from caudal to rostral), and the secondary prosencephalon (prosomeres p4–p6). The analyzed genes (Dlx2, Gbx2, Nkx2-1, Nkx2-2, Otx-2, and Shh) are expressed in restricted parts of the neuroepithelium. The hypothalamus is a part of two prosomeres, p4 and p5. According to the updated prosomeric model (Puelles and Rubenstein, 2015), these prosomeres are now two hypothalamo-telencephalic prosomeres (hp1 and hp2). The hp1 prosomere (former p4 prosomere) is called the peduncular hypothalamus (PHy), and the hp2 prosomere (former p5 prosomere) is the terminal hypothalamus (THy), which occupies the rostralmost part of the forebrain. H, rhombencephalon-hindbrain; I, isthmus; M, mesencephalon-midbrain; os, optic stalk; p, prosomere; r, rhombomere; sc, spinal cord; SP. Figure from the article by Rubenstein et al. (1994). Reprinted with permission from the American Association for the Advancement of Science.

Figure 2.

A schematic representation of forebrain subdivisions, expression patterns of TFs, and major hypothalamic and diencephalic nuclei originating from each prosomere. A, Forebrain subdivisions and expression patterns of TFs according to the prosomeric model. The developing STN can be found in the basal plate of the hp1 prosomere. Notice how the STN shares a set of TFs with other hypothalamic and diencephalic nuclei, as well as parts of the subpallium (i.e., basal ganglia). The telencephalon and the hypothalamus comprise the secondary prosencephalon. The diencephalic and the hypothalamic prosomeres have alar, basal, and floor plates. Also, in the prosomeric model, the hypothalamus is the rostralmost prosencephalic domain, and the STN is placed in the retromammillary area of the hp1 prosomere, the ventralmost part of the hypothalamus. ZLI is a transverse border between p2 and p3 prosomere. B, major hypothalamic and diencephalic nuclei originating from each prosomere. Parts of the substantia nigra and ventral tegmental area have diencephalic origin (Puelles, 2019), so they are parts of diencephalic prosomeres p1–p3. The dorsomedial nucleus originates from both peduncular and terminal hypothalamic domains. AHN, Anterior hypothalamic nucleus; DM, dorsomedial nucleus; Hb, habenula; MMN, mammillary nuclei; POA, preoptic area; PVN, paraventricular nucleus; RNp, parvocellular part of nucleus ruber; SN, substantia nigra; SON, supraoptic nucleus; Th, thalamus; TRN, thalamic reticular nucleus; VMH, ventromedial nucleus; VPM, ventral premammillary nucleus; C, Caudal; D, dorsal; R, rostral; V, ventral.

Figure 3.

Gene expression timelines during mouse embryonic development. Full lines represent mRNA expression detected by ISH in the hypothalamic retromammillary area/developing STN. Dashed lines represent the expression detected in other parts of the developing forebrain. For Foxa2, dashed lines indicate there are no conclusive results about its expression pattern in the developing STN (see text).