Developmental Genes and Malformations in the Hypothalamus

Abstract

The hypothalamus is a heterogeneous rostral forebrain region that regulates physiological processes essential for survival, energy metabolism, and reproduction, mainly mediated by the pituitary gland. In the updated prosomeric model, the hypothalamus represents the rostralmost forebrain, composed of two segmental regions (terminal and peduncular hypothalamus), which extend respectively into the non-evaginated preoptic telencephalon and the evaginated pallio-subpallial telencephalon. Complex genetic cascades of transcription factors and signaling molecules rule their development. Alterations of some of these molecular mechanisms acting during forebrain development are associated with more or less severe hypothalamic and pituitary dysfunctions, which may be associated with brain malformations such as holoprosencephaly or septo-optic dysplasia. Studies on transgenic mice with mutated genes encoding critical transcription factors implicated in hypothalamic-pituitary development are contributing to understanding the high clinical complexity of these pathologies. In this review article, we will analyze first the complex molecular genoarchitecture of the hypothalamus resulting from the activity of previous morphogenetic signaling centers and secondly some malformations related to alterations in genes implicated in the development of the hypothalamus.

Tangential Intrahypothalamic Migration of the Mouse Ventral Premamillary Nucleus and Fgf8 Signaling

“…The prosomeric model postulates there is a molecularly distinct basal acroterminal domain rostral to the M ( Puelles et al, 2012 ; Puelles and Rubenstein, 2015 ; Ferran et al, 2015 ). This rostromedian neuroepithelial locus may serve as a secondary organizer, due to its expression of Fgf family genes ( Ferran et al, 2015 ; Puelles, 2017 ; Diaz and Puelles, 2020 ). We show in Figures 12A,B Allen Developing Mouse Brain Atlas images illustrating mouse acroterminal Fgf8 transcripts at E11.5 and E13.5, encompassing the period in which the VPM migration occurs.…”

“…Basal ventralization can explain the pattern of topologically parallel longitudinal domains (e.g., TuD, TuI, TuV, PM, M, M floor; Figures 1A,C ). In its turn, the acroterminal area, which is an apparent median source of rostralizing morphogens of the FGF family ( Ferran et al, 2015 ; Puelles, 2017 ; Diaz and Puelles, 2020 ), can explain the rostrocaudal differences found between Tu and RTu, PM and PRM, or M and RM.…”

“…Some previous studies showed alterations in the pituitary and neuropeptide producing areas in the basal tuberal hypothalamus of Fgf8 hypomorphs ( Brooks et al, 2010 ; McCabe et al, 2011 ; Rodriguez et al, 2015 ). It is not surprising that FGF8 has a role in the developing hypothalamus due to its high level of acroterminal expression (jointly with other Fgf family members; see Ferran et al, 2015 ; Diaz and Puelles, 2020 ), matching with Fgf8 receptors, mainly Fgfr2, distributed throughout the hypothalamic basal plate. Even though reduced in its cellularity, a recognizable VPM nucleus appears in the hypoplasic Tu area at E18.5 (present results).…”

“…It is separated from the latter by the histaminergic tuberomamillary area and the perimamillary band (the latter contains the conventional dorsal premamillary nucleus; DPM; Figure 1C ). Its rostral infundibular relationship abuts the acroterminal hypothalamic domain (rostral end of the hypothalamus in the prosomeric model; Puelles et al, 2012 ; Puelles and Rubenstein, 2015 ; Diaz and Puelles, 2020 ). The VPM contains excitatory glutamatergic neurons, which display a diversity of molecular profiles, possibly related to its different projections ( Ziegler et al, 2002 ; Mickelsen et al, 2020 ).…”

The Enigmatic Reissner’s Fiber and the Origin of Chordates

“…In late vertebrate development, RF is secreted by the subcommissural organ (SCO), a dorsal circumventricular organ located below the posterior commissure in the dorsal neural tube (the roof plate) at the M-D junction (dorsal prosomer P1 ;Nieuwenhuys, 1988;Meiniel et al, 1996;Grondona et al, 2012;Puelles, 2018;Muñoz et al, 2019;Diaz and Puelles, 2020; Figure 3). The SCO has a complex histological structure containing specialized, elongated ependymal cells with a basal process contacting the perivascular space that receives synaptic connections and an apical process that reaches the central canal and secretes RF, among other components (Rodríguez et al, 1992).…”