Modeling the complex etiology of holoprosencephaly in mice

Abstract

Holoprosencephaly (HPE) is a common developmental defect caused by failure to define the midline of the forebrain and/or midface. HPE is associated with heterozygous mutations in Nodal and Sonic hedgehog (SHH) pathway components, but clinical presentation is highly variable, and many mutation carriers are unaffected. It is therefore thought that such mutations interact with more common modifiers, genetic and/or environmental, to produce severe patterning defects. Modifiers are difficult to identify, as their effects are context-dependent and occur within the complex genetic and environmental landscapes that characterize human populations. This has made a full understanding of HPE etiology challenging. We discuss here the use of mice, a genetically tractable model sensitive to teratogens, as a system to address this challenge. Mice carrying mutations in human HPE genes often display wide variations in phenotypic penetrance and expressivity when placed on different genetic backgrounds, demonstrating the existence of silent HPE modifier genes. Studies with mouse lines carrying SHH pathway mutations on appropriate genetic backgrounds have led to identification of both genetic and environmental modifiers that synergize with the mutations to produce a spectrum of HPE phenotypes. These models favor a scenario in which multiple modifying influences-both genetic and environmental, sensitizing and protective-interact with bona fide HPE mutations to grade phenotypic outcomes. Despite the complex interplay of HPE risk factors, mouse models have helped establish some clear concepts in HPE etiology. A combination of mouse and human cohort studies should improve our understanding of this fascinating and medically important issue.

The Hedgehog Co-Receptor BOC Differentially Regulates SHH Signaling During Craniofacial Development

“…Gli1 expression. The variability in the HPE phenotypes of our mutants could be explained due to multiple 292 genetic and non-genetic risk factors (Hong and Krauss, 2018). In particular, the variable severity across the 293 phenotypes in our mutants could arise from stochastic changes in the establishment or response to the SHH 294 morphogen gradient in the neuroepithelium, neural crest-derived mesenchyme, and/or surface ectoderm.…”

“…Aberrant HH pathway activity results in severe birth 19 defects including Holoprosencephaly (HPE), a defect characterized by the failure of the division of the 20 embryonic forebrain into two cerebral hemispheres (Muenke and Beachy, 2000). HPE is one of the most 21 common birth defects in humans, estimated to affect as many as 1 in 250 embryos (Hong and Krauss, 2018). 22…”

Topological atlas of the hypothalamus in adult rhesus monkey

“…A specific subset of malformations known as holoprosencephaly describes a spectrum of interhemispheric cleavage malformations of the forebrain ranging from impaired to complete absence of cleavage. The etiology of holoprosencephaly can be traced in part to specific abnormalities in the Shh (sonic hedgehog) signaling pathway in the early tissues of the rostral neural plate (reviewed in Hong and Krauss 2018;Andreu-Cervera et al 2019). Consequently, there are massive patterning defects in the hypothalamus and later-appearing structures, including the telencephalon, the eyes, the infundibulum, and the neurohypophysis portion of the pituitary gland.…”

A forebrain undivided: Unleashing model organisms to solve the mysteries of holoprosencephaly

“…Fetal alcohol exposure is the best‐characterized environmental risk factor for HPE in humans and has been successfully modeled in mouse . In the mouse model, alcohol exposure has been shown specifically to reduce Hh signaling during forebrain specification, perhaps indirectly by preventing normal formation of the PCP …”

“…70,81 In the mouse model, alcohol exposure has been shown specifically to reduce Hh signaling during forebrain specification, perhaps indirectly by preventing normal formation of the PCP. 82 Alcohol also interferes with cellular entry of folate, [83][84][85] an essential carrier of one-carbon groups required for nucleotide synthesis and DNA methylation. Recently, Toriyama et al 86 reported a novel role for folate in primary ciliogenesis, through methylation of a ciliary component septin2.…”