Pathogenesis of holoprosencephaly

Abstract

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.

Figure 1. Development of the mammalian forebrain.

(A–C) At early primitive-streak stage, epiblast cells ingress through the primitive streak (PS) to form the mesoderm. Medial sagittal section of E6.5 mouse (A) and Carnegie Stage 7 (CS7) human (B) embryos with anterior to the left. (C) Dorsal view of a CS7 human embryo. AVE, anterior visceral endoderm; VE, visceral endoderm. (D) At early somite stage (E8.5 for mouse; CS10 for human), the neural ectoderm has been specified into different regions along the anterior-posterior axis and the axial mesoderm is underlying the midline of the neural ectoderm. ANC, anterior notochord; PFB, prospective forebrain (or ANE); PH, prospective hindbrain; PM, prospective midbrain; PNC, posterior notochord; PSC, prospective spinal chord. (E) Neural tube closure occurs at around the 15-somite stage (E9.0 for mouse; CS11 for human). The forebrain gets further regionalized into telencephalon, diencephalon, and prospective hypothalamus (PH). OV, optic vesicle. (F) Approximately at E10.5 in the mouse or at CS14 in human embryos, the expanding telencephalon bifurcates dorsally to form the two hemispheres and gets patterned into dorsal telencephalon (DT) and ventral telencephalon (VT). (G and I) Lateral views of adult mouse (G) and human brain (I). OB, olfactory bulb. Black dashed lines in G and I indicate the location of coronal sections shown in H and J. (H and J) Coronal sections of adult mouse (H) and human brain (J). BG, basal ganglia; CiC, cingulate cortex; CoC, corpus callosum; LV, lateral ventricle.

Figure 2. Clinical manifestations of HPE.

(A–I) Coronal images of control and HPE brains from anterior (A, D, and G) to posterior (C, F, and I). (A–C) In the control brain, the two hemispheres are separated completely (arrow in A) and the septum (arrow in B) and the corpus callosum (arrowhead in B) are present. (D–F) In alobar HPE, a single cerebral ventricle is present and the interhemispheric fissure is completely absent. (G–I) In semilobar HPE, the two hemispheres are incompletely separated (arrow in G) and the septum and corpus callosum are absent (arrow and arrowhead in H, respectively). (J and K) Horizontal images of control (J) and lobar HPE (K). The septum is present in the control brain (arrow in J); however, it is partially absent in the lobar HPE brain (arrow in K). (L) Sagittal image of a MIH brain. The genu and splenium of the corpus callosum are present (arrows in L); however, the corpus callosum is absent at the region lacking the interhemispheric fissure (arrowhead in L). (M–O) Craniofacial defects associated with HPE. (M) Alobar HPE with cyclopia and proboscis. (N) Semilobar HPE with microcephaly and cleft lip and palate. (O) Semilobar HPE with ocular hypotelorism and midface hypoplasia. (P and Q) Microforms of HPE. (P) Absence of nasal bones and cartilage with a narrow nasal bridge. (Q) Single central maxillary incisor. (R) MIH patient with normal facial appearance. A–C and G–I are reprinted with permission from Cerebral cortex (17); D–F are reprinted with permission from American Journal of Medical Genetics (18); J is reprinted with permission from Brain Maps (111); K is reprinted with permission from MedPix (112); L is reprinted with permission from American Journal of Neuroradiology (23); M and O are reprinted with permission from Human Molecular Genetics (19); N and P are reprinted with permission from Human Molecular Genetics (20); Q is reprinted with permission from Nature Genetics (21); and R is reprinted with permission from Human Molecular Genetics (24).

Figure 3. Mouse models of HPE.

(A and B) Chd^–/–Nog^–/– embryo exhibiting alobar HPE–like phenotype: cyclopia (arrow in A) and proboscis (arrowhead in A). (B) Coronal section of Chd^–/–Nog^–/– embryo highlighting the single cerebral ventricle (arrow). (C and D) Six3^+/kiShh^+/– embryos exhibit semilobar HPE–like phenotype: agenesis of philtrum (arrow in C), lack of corpus callosum (arrowhead in D), and a single telencephalic ventricle anteriorly (arrow in D). (D) Coronal section of a Six3^+/kiShh^+/– embryo. (E) Image of an adult Cdo^–/– mouse exhibiting microforms of HPE: dysgenesis of philtrum (arrow) and single central maxillary incisor (arrowhead). (F) Coronal section of an ShhN/+ embryo exhibiting MIH-like phenotype: lack of dorsal telencephalic midline structures (arrow in F) and relatively normal ventral telencephalic structures. A and B are reprinted with permission from Nature (60); C and D are reprinted with permission from Developmental Cell (65); E is reprinted with permission from Current Biology (91); F is reprinted with permission from Human Molecular Genetics (101).

Figure 4. Signaling pathways involved in the pathogenesis of HPE.

(A) Nodal signaling pathway. (B) Bmp signaling pathway. (C) Shh signaling pathway. ActR2A, activin A receptor, type 2A; BmpR2, Bmp receptor 2; Disp, dispatched; Ptch, patched; Smo, smoothened; Tld, tolloid.

Figure 5. Mechanistic model of telencephalon development in normal and HPE conditions.

(A) Model of normal mammalian telencephalic development. On the left side, the PrCP is represented by a white rectangle. The blue square around it highlights those steps known to be critical in the pathogenesis of alobar HPE. Toward the right side of the diagram, genes known to be important during subsequent steps of forebrain development are indicated. The orange rectangle highlights steps and genes important for semilobar HPE, the green rectangle highlights those important for MIH, and the gray rectangle highlights those important for microforms of HPE. Solid lines represent those processes that have been demonstrated and dashed lines represent those processes that have not yet been directly proved. To better understand the regional relationships between some of those critical genes, their normal expression patterns in the telencephalon at E9.0 and E10.5 are illustrated in B and C, respectively. C is adapted with permission from Journal of Neuropathology and Experimental Neurology (106). Hnf3b, hepatocyte nuclear factor 3β; Otx2, orthodenticle homolog 2; Pax6, paired box gene 6; Wnt8b, wingless-related MMTV integration site 8b.