A new scenario of hypothalamic organization: rationale of new hypotheses introduced in the updated prosomeric model

Abstract

In this essay, we aim to explore in depth the new concept of the hypothalamus that was presented in the updated prosomeric model (Puelles et al., 2012b; Allen Developing Mouse Brain Atlas). Initial sections deal with the antecedents of prosomeric ideas represented by the extensive literature centered on the alternative columnar model of Herrick (1910), Kuhlenbeck (1973) and Swanson (1992, 2003); a detailed critique explores why the columnar model is not helpful in the search for causal developmental explanations. In contrast, the emerging prosomeric scenario visibly includes many possibilities to propose causal explanations of hypothalamic structure relative to both anteroposterior and dorsoventral patterning mechanisms, and insures the possibility to compare hypothalamic histogenesis with that of more caudal parts of the brain. Next the four major changes introduced in the organization of the hypothalamus on occasion of the updated model are presented, and our rationale for these changes is explored in detail. It is hoped that this example of morphological theoretical analysis may be useful for readers interested in brain models, or in understanding why models may need to change in the quest for higher consistency.

A novel floor plate boundary defined by adjacentEn1andDbx1microdomains distinguishes midbrain dopamine and hypothalamic neurons

“…One possibility is that the mdFP is subdivided along the A-P axis into lineage-restricted microdomains. Such a possibility is indeed depicted in prosomere-based models of the segmentally divided embryonic CNS (Björklund and Dunnett, 2007;Puelles and Rubenstein, 2015;Rubenstein et al, 1994;Smidt and Burbach, 2007;Smits et al, 2006Smits et al, , 2013, but evidence for such microdomains within the Shh + /Foxa2 + /Lmx1a + mdFP is limited. These models of the subdivided mdFP are based on prosomeric gene expression patterns in more dorsal CNS structures, and these genes are often not expressed in the mdFP.…”

“…In the early embryo, differentiating Th + DA neurons are observed in the midbrain with a caudal limit at the MHB. The anterior limit of this Th + DA cohort is approximately near the base of the zona limitans intrathalamica (ZLI), the boundary between presumptive developmental segmental units, prosomeres 2 and 3 (p2 and p3) (Joksimovic et al, 2009;Nouri et al, 2015;Puelles and Rubenstein, 2015). Because these neurons appear to be generated from the midbrain as well as presumptive p1, p2 and p3, some have called these mesodiencephalic DA neurons (Puelles and Rubenstein, 2015;Veenvliet and Smidt, 2014), as opposed to midbrain DA neurons (Arenas et al, 2015;Blaess and Ang, 2015).…”

“…Accurate settling of these disputes is crucial, as they ultimately determine the numbers and types of neurons produced, with consequent outcomes on physiology and behavior. Recent papers have relied on gene expression patterns and fate mapping, to develop more sophisticated maps of the developing CNS (Bedont et al, 2015;Puelles et al, 2013;Puelles and Rubenstein, 2015;Shimogori et al, 2010;Swanson, 2012;Thompson et al, 2014). Despite significant progress, these recent reviews acknowledge that current models are imperfect and that further evaluation using modern molecular tools is imperative.…”

“…Because these neurons appear to be generated from the midbrain as well as presumptive p1, p2 and p3, some have called these mesodiencephalic DA neurons (Puelles and Rubenstein, 2015;Veenvliet and Smidt, 2014), as opposed to midbrain DA neurons (Arenas et al, 2015;Blaess and Ang, 2015). Interestingly, most of the currently known DA progenitor markers, including Shh, Wnt1, Otx2, Neurog2, Lmx1a/b, Foxa1/2 and Msx1, among others, are expressed rostrally, well beyond the ZLI, into presumptive p3 of the diencephalon Andersson et al, 2006;Ellisor et al, 2012;Lahti et al, 2012;Nouri et al, 2015;Puelles and Rubenstein, 2015). Why DA neurons are not produced from the entire A-P axis of the Shh + /Foxa2 + /Lmx1a + mdFP, despite the presence of key signaling molecules and transcription factors, is a conundrum.…”

“…The anterior limit of this Th + DA cohort is approximately near the base of the zona limitans intrathalamica (ZLI), the boundary between presumptive developmental segmental units, prosomeres 2 and 3 (p2 and p3) (Joksimovic et al, 2009;Nouri et al, 2015;Puelles and Rubenstein, 2015). Because these neurons appear to be generated from the midbrain as well as presumptive p1, p2 and p3, some have called these mesodiencephalic DA neurons (Puelles and Rubenstein, 2015;Veenvliet and Smidt, 2014), as opposed to midbrain DA neurons (Arenas et al, 2015;Blaess and Ang, 2015). Interestingly, most of the currently known DA progenitor markers, including Shh, Wnt1, Otx2, Neurog2, Lmx1a/b, Foxa1/2 and Msx1, among others, are expressed rostrally, well beyond the ZLI, into presumptive p3 of the diencephalon Andersson et al, 2006;Ellisor et al, 2012;Lahti et al, 2012;Nouri et al, 2015;Puelles and Rubenstein, 2015).…”