Patterning of the basal telencephalon and hypothalamus is essential for guidance of cortical projections

Abstract

We have investigated the mechanisms that control the guidance of corticofugal projections as they extend along different subdivisions of the forebrain. To this aim, we analyzed the development of cortical projections in mice that lack Nkx2-1, a homeobox gene whose expression is restricted to two domains within the forebrain: the basal telencephalon and the hypothalamus. Molecular respecification of the basal telencephalon and hypothalamus in Nkx2-1-deficient mice causes a severe defect in the guidance of layer 5 cortical projections and ascending fibers of the cerebral peduncle. These axon tracts take an abnormal path when coursing through both the basal telencephalon and hypothalamus. By contrast, loss of Nkx2-1 function does not impair guidance of corticothalamic or thalamocortical axons. In vitro experiments demonstrate that the basal telencephalon and the hypothalamus contain an activity that repels the growth of cortical axons, suggesting that loss of this activity is the cause of the defects observed in Nkx2-1 mutants. Furthermore, analysis of the expression of candidate molecules in the basal telencephalon and hypothalamus of Nkx2-1 mutants suggests that Slit2 contributes to this activity.

Characterization of Hypothalamic MCH Neuron Development in a 3D Differentiation System of Mouse Embryonic Stem Cells

“…5 B ). Although Nkx2.1 can be expressed in telencephalic progenitors ( Shimamura et al, 1995 ; Marín et al, 2002 ; Fig. 5 A ), the pan-telencephalic marker Foxg1 was almost absent in the SAG-treated aggregates ( Fig.…”

“…A , The regional expression of transcription factors in the telencephalon and anterior diencephalon of embryonic mouse brain around E12. The indicated expression patterns are based on the published literature ( Shimamura et al, 1995 ; Marín et al, 2002 ; Shimogori et al, 2010 ; Lu et al, 2013 ; Díaz et al, 2014 ; Ferran et al, 2015 ). Cx, cortex; MGE, medial ganglionic eminence; OS, optic stalk; PTh, prethalamus; zli, zona limitans intrathalamica.…”

Gli2-Mediated Shh Signaling Is Required for Thalamocortical Projection Guidance

“…The morphogene Fgf10 has been recently related to this repulsive effect ( Liu et al, 2020 ). Indeed, in Nkx2.1 mutant, the absence of the basal Hy does not impair thalamocortical projections due to the normal specification of the alar Hy ( Marín et al, 2002 ). In the Gli2 mutant, the basal Hy is severely altered but not absent, this could explain that in our case, the TCAs are able to find a permissive territory to invade.…”

“…This is translated into the incapability of the TCAs to go across this territory. Surprisingly, a medial transformation into LGE with an expansion of the striatum, by the loss of Nkx2.1 function ( Sussel et al, 1999 ), described the normal generation of the thalamocortical projections ( Marín et al, 2002 ). A reasonable explanation for these two opposite phenotypes is that in the Nkx2.1 mutant, the LGE is completely unaffected and therefore the needed corridor is correctly formed.…”

Hypothalamic TTF-1 orchestrates the sensitivity of leptin

“…TTF-1 plays a critical role in the development of the diencephalic brain regions [ 7 ]. Mice carrying the null mutation of the TTF-1 gene are stillborn due to lung failure, along with severe malformation or absence of some hypothalamic structures such as the ventral third ventricle and periventricular nuclei [ 8 , 9 ]. In line with this notion, we have found the presence of TTF-1 expression in several discrete hypothalamic nuclei, where it is involved in neural or neuroendocrine physiological mechanisms important in the control of body homeostasis [ 7 , 10 , 11 ].…”