Specification of posterior hypothalamic neurons requires coordinated activities of Fezf2, Otp, Sim1a and Foxb1.2

Abstract

SUMMARYThe hypothalamus is a key integrative center in the brain that consists of diverse cell types required for a variety of functions including homeostasis, reproduction, stress response, social and cognitive behavior. Despite our knowledge of several transcription factors crucial for hypothalamic development, it is not known how the wide diversity of neuron types in the hypothalamus is produced. In particular, almost nothing is known about the mechanisms that specify neurons in the posteriormost part of the hypothalamus, the mammillary area. Here, we investigated the specification of two distinct neuron types in the mammillary area that produce the hypothalamic hormones Vasoactive intestinal peptide (Vip) and Urotensin 1 (Uts1). We show that Vip-and Uts1-positive neurons develop in distinct domains in the mammillary area defined by the differential expression of the transcription factors Fezf2, Otp, Sim1a and Foxb1.2. Coordinated activities of these factors are crucial for the establishment of the mammillary area subdomains and the specification of Vip-and Uts1-positive neurons. In addition, Fezf2 is important for early development of the posterior hypothalamus. Thus, our study provides the first molecular anatomical map of the posterior hypothalamus in zebrafish and identifies, for the first time, molecular requirements underlying the specification of distinct posterior hypothalamic neuron types.

Automated deep-phenotyping of the vertebrate brain

“…When otpb and th are virtually co-registered with fezf2 , they are located in an anterior/lateral position relative to fezf2 (Figure 4F). This distinctive arrangement of fezf2 and otpb in the posterior hypothalamus has been described previously using two-color fluorescent in situ hybridization (Wolf and Ryu, 2013). In fezf2 mutants, fezf2 expression is lost along the midline while simultaneously expanding laterally and anteriorly into regions normally expressing otpb and th (Figure 4F).…”

“…Previous work shows that fezf2 is required for expression of otpb and the closely related otpa. Otp genes in turn act as negative regulators of fezf2 (Yang et al, 2012; Wolf and Ryu, 2013). Taken together with our observations, this suggests fezf2 could be transiently expressed in anterior/lateral regions of the hypothalamus that eventually become otp positive and fezf2 negative.…”

A New 3p14.2 Microdeletion in a Patient with Intellectual Disability and Language Impairment: Case Report and Review of the Literature

“…The respective codified proteins proved to be linked to brain development and function. The FEZF2 gene (FEZ family zinc finger protein 2) encodes a transcriptional factor necessary for the specification of corticospinal neuron and connectivity [Yang et al, 2012;Wolf and Ryu, 2013]. The CADPS gene (calcium-dependent activator protein for secretion 1) encodes a neuroendocrine-specific cytosolic and peripheral membrane protein that is required for Ca 2+ -regulated exocytosis of the secretory vesicle.…”

Specification of Select Hypothalamic Circuits and Innate Behaviors by the Embryonic Patterning Gene Dbx1

“…Shh, BMPs, Wnts) and intrinsic (e.g. bHLH and homeodomain-containing transcription factors such as Lhx2 , Rax , Nkx2.1 , Mash1 and Otp ) factors are essential for either regional patterning of the hypothalamus or specification of neuronal subpopulations (Caqueret et al, 2006; McNay et al, 2006; Lu et al, 2013; Peng et al, 2012; Shimogori et al, 2010; Szabó et al, 2009; Wang et al, 2012; Wolf and Ryu, 2013; reviewed in Hoch et al, 2009; Kaji and Nonogaki, 2013; Lee and Blackshaw, 2014; Salvatierra et al, 2014). Here, we find that Dbx1 is required for the specification of orexigenic Npy+/Agrp+ neurons in the Arc and Pmch+ and Hcrt+ output neurons in the LH.…”