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Holoprosencephaly (HPE), the most common human forebrain malformation, occurs in 1 in 250 fetuses and 1 in 16,000 live births. HPE is etiologically heterogeneous, and its pathology is variable. Several mouse models of HPE have been generated, and some of the molecular causes of different forms of HPE and the mechanisms underlying its variable pathology have been revealed by these models. Herein, we summarize the current knowledge on the genetic alterations that cause HPE and discuss some important questions about this disease that remain to be answered.
Nonstandard abbreviations used: ANE, anterior neuroectoderm; Bmp, bone morphogenetic protein; Cdo, cell adhesion molecule-related/downregulated by oncogenes; Chd, chordin; FOXH1, forkhead box H1; Gas1, growth arrest-specific 1; Gdf1, growth differentiation factor 1; GLI2, glioma-assotiated oncogene family zinc finger 2; HPE, holoprosencephaly, LGE, lateral ganglionic eminence; MGE, median ganglionic eminence; MIH, middle interhemispheric variant of HPE; Nkx2.1, NK2 homeobox 1; Nog, noggin; PrCP, prechordal plate; SHH, sonic hedgehog; SIX3, SIX homeobox 3; TDGF1, teratocarcinoma-derived growth factor 1; TGIF, TGF-β-induced factor homeobox; Tsg, twisted gastrulation; ZIC2, zinc finger protein of the cerebellum 2.
Development of the forebrain
Holopt osencephaly (HPE) is a developmental disorder, and interpretation of its pathogenesis requires a clear understanding of normal forebrain development (Figure 1). During early embryogenesis, the mouse blastocyst develops into a bilayered conical structure, with the epiblast inside and the visceral endoderm outside (Figure IA). As development progresses, a group of visceral endodermal cells located at the distal tip of the egg cylinder moves anteriorly to form the anterior visceral endoderm, while the primitive streak forms at the posterior epiblast (Figure IA). Subsequently, gastrulation occurs and epiblast cells ingress through the primitive streak (1, 2) (Figure IA). As gastrulation progresses, neural specification results in the formation of the neural plate (3-5). The neural plate initially has an anterior identity (3-5), but signaling molecules from the posterior epiblast and lateral mesoderm subsequently induce posterior characteristics in this structure. Antagonists secreted mainly by the anterior visceral endoderm maintain and stabilize the fate of the anterior neuroectoderm (ANE), from which the forebrain arises (3, 4) (Figure 1, A and D).
Unlike the conical structure of the mouse blastocyst, that of the human blastocyst is a flat, bilayered disc (6) (Figure 1, B and C). Despite...