Roles of Pax-6 in murine diencephalic development

Abstract

Pax-6 is one of the earliest regulatory genes to be expressed in the diencephalon. We tested whether normal Pax-6 protein is required for early diencephalic development by examining morphology, precursor proliferation and patterns of regulatory gene expression in the embryonic diencephalon of Small-eye mice (Pax-6 mutants). In Small-eye mice, diencephalic morphology was abnormal at all the embryonic ages studied (days 10.5, 12.5 and 14.5). Regional differences in diencephalic cell density were lost, the diencephalon/mesencephalon boundary was unclear and the third ventricle was enlarged. We estimated diencephalic proliferative rates after labelling with bromodeoxyuridine and found that they were abnormally low in mutants aged embryonic day 10.5. In older mutants, the diencephalon contained fewer cells than normal. In wild-type E14.5 diencephalon, Pax-6, Dlx-2 and Wnt-3 are expressed in discrete regions along the rostrocaudal and dorsoventral axes. In situ hybridizations for these genes in E14.5 Small-eye mice revealed discrete zones of diencephalic expression that had similar relative positions to those in wild-type mice. Some differences of detail in their expression were seen: Pax-6 had an expanded rostral domain of expression and an abnormally indistinct caudal boundary; Dlx-2 had a diffuse, rather than a sharp, caudal boundary of expression; the normally high dorsal midline expression of Wnt-3 was lost. We conclude that normal expression of Pax-6 is required for the correct regulation of diencephalic precursor proliferation. Pax-6 may also control some aspects of diencephalic differentiation, but its mutation in Small-eye mice does not preclude the development of a degree of diencephalic regionalization resembling that in normal mice.

Ancestral role of Pax6 in chordate brain regionalization

“…The molecular markers of the mesencephalon expand into pretectum and the identity of the pretectum is partially shifted towards that of the mesencephalon ( 21 ). Additionally, the expression markers of the thalamus are downregulated, and genes normally confined to the ZLI are ectopically expressed in the surrounding regions ( 20, 55, 56 ).…”

“…Homozygous Sey mutants are not viable; the embryos exhibit profound brain and olfactory malformations ( 5 ). Pax6 plays a role in establishing boundaries between regions of the central nervous system in the anteroposterior axis, at least in part, due to the regulation of homeobox-containing genes such as En1 , Pax2 , and Lhx1 ( 20–22 ). The boundary between cortical and striatal regions of the telencephalon is dramatically altered in Sey mutants: radial glial fascicles do not form at the border, and the normal expression of R-cadherin and tenascin-C at the border is lost suggesting that Pax6 regulates boundary formation between developing forebrain regions ( 23 ).…”

Developmental Cues and Molecular Drivers in Myelinogenesis: Revisiting Early Life to Re-Evaluate the Integrity of CNS Myelin

“…Interestingly, overexpression of inhibitor of DNA binding (ID) 2 and ID4 enhances proliferation [ 88 , 89 ]. Similarly, expression of SHH, HGF, neurotrophin-4 (NT-4), noggin, superoxide dismutase 1 (SOD1), neurotrophin-3 (NT-3), achaete-scute family bHLH transcription factor 1 (ASCL1), PAX6, CLDN1, and CLDN3 promotes the proliferation process [ 41 , 54 , 70 , 90 , 91 , 92 , 93 , 94 , 95 ].…”

Pax6 loss alters the morphological and electrophysiological development of mouse prethalamic neurons

“…Most, if not all, prethalamic progenitors are Pax6-positive but, unusually, strong Pax6 expression is retained by many post-mitotic neurons in the embryonic prethalamus ( Duan et al, 2013 ; Caballero et al, 2014 ). Constitutive deletion of Pax6 all but prevents the formation of the prethalamus, precluding an analysis of the consequences of its loss for developing prethalamic neurons ( Stoykova et al, 1996 ; Warren and Price, 1997 ).…”