Development of neuroendocrine lineages requires the bHLH–PAS transcription factor SIM1

Abstract

The bHLH-PAS transcription factor SIM1 is expressed during the development of the hypothalamic-pituitary axis in three hypothalamic nuclei: the paraventricular nucleus (PVN), the anterior periventricular nucleus (aPV), and the supraoptic nucleus (SON). To investigate Sim1 function in the hypothalamus, we produced mice carrying a null allele of Sim1 by gene targeting. Homozygous mutant mice die shortly after birth. Histological analysis shows that the PVN and the SON of these mice are hypocellular. At least five distinct types of secretory neurons, identified by the expression of oxytocin, vasopressin, thyrotropin-releasing hormone, corticotropin-releasing hormone, and somatostatin, are absent in the mutant PVN, aPV, and SON. Moreover, we show that SIM1 controls the development of these secretory neurons at the final stages of their differentiation. A subset of these neuronal lineages in the PVN/SON are also missing in mice bearing a mutation in the POU transcription factor BRN2. We provide evidence that, during development of the Sim1 mutant hypothalamus, the prospective PVN/SON region fails to express Brn2. Our results strongly indicate that SIM1 functions upstream to maintain Brn2 expression, which in turn directs the terminal differentiation of specific neuroendocrine lineages within the PVN/SON.[Key Words: SIM; hypothalamus; paraventricular nucleus; supraoptic nucleus; hormones]Received June 10, 1998; revised version accepted August 21, 1998.The hypothalamus integrates a variety of signals from the brain and the periphery to modulate secretion by the pituitary of peptidic hormones involved in maintaining homeostasis. A large body of work, starting with the discovery of oxytocin and vasopressin (Du Vigneaud 1955), has led to the identification of numerous neuropeptides secreted by hypothalamic and pituitary cells. The availability of these markers has allowed a detailed characterization of the different cell types found in the hypothalamus and the pituitary and the delineation of their physiological role. This fundamental work has made the hypothalamic-pituitary axis an advantageous system to study the mechanisms involved in generating cell diversity in the central nervous system (CNS).The neuroendocrine system consists of two sets of hypothalamic neurons: the magnocellular and the parvocellular neurons (for review, see Swanson and Sawchenko 1983;Swanson 1986;Sawchenko et al. 1992). The magnocellular neurosecretory system projects to the posterior pituitary where it releases vasopressin (AVP) and oxytocin (OT) directly into the general circulation. Vasopressin participates in the control of blood volume, osmolality, and pressure, whereas OT promotes parturition and lactation. The magnocellular neurons are located in two nuclei of the anterior hypothalamus, the paraventricular (PVN) and the supraoptic (SON) nuclei. Within the PVN and the SON, AVP and OT are produced by mutually exclusive sets of neurons. The sum of AVPand OT-producing cells corresponds to the total number of magnocellular neurons, indicating t...

Requirement of the orphan nuclear receptor SF-1 in terminal differentiation of ventromedial hypothalamic neurons

“…In addition, our findings are complementary to the known role of the bHLH-PAS transcription factor, SIM1 in the development of several hypothalamic nuclei, including the PVN, supraoptic nucleus (SON), and anterior periventricular nucleus (aPV). All of these nuclei share a common precursor and SIM1 function is required for the terminal differentiation of PVN/SON/aPV precursors (Michaud et al, 1998;Michaud, 2001). In the absence of SIM1, PVN/SON/aPV common precursors persist initially, but are subsequently lost upon terminal differentiation.…”

Targeted mutation of the murine arylhydrocarbon receptor nuclear translocator 2 ( Arnt2 ) gene reveals partial redundancy with Arnt

“…In contrast, parvocellular neurons in the PVN and anterior periventricular nucleus secrete thyrotropin-releasing hormone (TRH), corticotropin-releasing hormone (CRH), and somatostatin (SS) into the portal vasculature connecting the median eminence to the anterior pituitary. In Sim1 Ϫ/Ϫ embryos, these lineages fail to differentiate or survive, as indicated by decreased expression of neuropeptide-encoding genes (14). Furthermore, the expression of transcripts encoding BRN2, a POU-domain transcription factor essential for the development of AVP, OT, and CRH-producing neurons (21), is downregulated in Sim1 Ϫ/Ϫ embryos, placing Brn2 expression downstream of Sim1 (14).…”

“…In Sim1 Ϫ/Ϫ embryos, these lineages fail to differentiate or survive, as indicated by decreased expression of neuropeptide-encoding genes (14). Furthermore, the expression of transcripts encoding BRN2, a POU-domain transcription factor essential for the development of AVP, OT, and CRH-producing neurons (21), is downregulated in Sim1 Ϫ/Ϫ embryos, placing Brn2 expression downstream of Sim1 (14). Identical phenotypes were reported for Arnt2-deficient c 112k mutants, leading Michaud et al (16) to propose that ARNT2 and SIM1 form functional heterodimers in vivo.…”

“…Interestingly, perinatal lethality has also been reported for mice with a targeted mutation of another bHLH-PAS gene, Sim1 (14), and is associated with loss of neuroendocrine lineages that regulate pituitary function by secreting oxytocin (OT), arginine-vasopressin (AVP), thyrotropin-releasing hormone (TRH), corticotropinreleasing hormone (CRH), and somatostatin (SS). Expression of genes encoding these five hormones is down-regulated in Sim1 Ϫ/Ϫ embryos and is correlated with the death, or change in fate, of the corresponding neurons (14). The perinatal lethality of both Sim1 Ϫ/Ϫ and Arnt2 Ϫ/Ϫ embryos raised the possibility that SIM1 and ARNT2 proteins may interact in vivo.…”

Dynamic expression of Thyrotropin‐releasing hormone in the mouse definitive endoderm

“…The presence of TRH throughout the central nervous system as well as in numerous peripheral organs supports a diverse range of roles for this molecule outside of the traditional HPT axis, including a potential role as a neurotransmitter. During mouse embryogenesis, Trh mRNA has been detected in the neural folds at E8.0, at the midbrain-hindbrain junction from E8.5 to E10.5, and in the developing hypothalamus from E11.5 to E18.5 (Schonemann et al, 1995;Michaud et al, 1998Michaud et al, , 2000Acampora et al, 1999;Wang and Lufkin, 2000;Keith et al, 2001;Backman et al, 2003;Goshu et al, 2004;Caqueret et al, 2006;Jukkola et al, 2006). Despite the critical role of TRH in regulating the HPT axis and its expression in developing neural structures, mice deficient in Trh are viable and fertile (Yamada et al, 1997(Yamada et al, , 2003.…”