Mutations in DCC cause isolated agenesis of the corpus callosum with incomplete penetrance

Brain malformations involving the corpus callosum are common in children with developmental disabilities. We identified DCC mutations in four families and five sporadic individuals with isolated agenesis of the corpus callosum (ACC) without intellectual disability. DCC mutations result in variable dominant phenotypes with decreased penetrance, including mirror movements and ACC associated with a favorable developmental prognosis. Possible phenotypic modifiers include the type and location of mutation and the sex of the individual

Development of body, head and brain features in the Australian fat-tailed dunnart (Sminthopsis crassicaudata; Marsupialia: Dasyuridae); A postnatal model of forebrain formation

Most of our understanding of forebrain development comes from research of eutherian mammals, such as rodents, primates, and carnivores. However, as the cerebral cortex forms largely prenatally, observation and manipulation of its development has required invasive and/or ex vivo procedures. Marsupials, on the other hand, are born at comparatively earlier stages of development and most events of forebrain formation occur once attached to the teat, thereby permitting continuous and non-invasive experimental access. Here, we take advantage of this aspect of marsupial biology to establish and characterise a resourceful laboratory model of forebrain development: the fat-tailed dunnart (Sminthopsis crassicaudata), a mouse-sized carnivorous Australian marsupial. We present an anatomical description of the postnatal development of the body, head and brain in dunnarts, and provide a staging system compatible with human and mouse developmental stages. As compared to eutherians, the orofacial region develops earlier in dunnarts, while forebrain development is largely protracted, extending for more than 40 days versus ca. 15 days in mice. We discuss the benefits of fat-tailed dunnarts as laboratory animals in studies of developmental biology, with an emphasis on how their accessibility in the pouch can help address new experimental questions, especially regarding mechanisms of brain development and evolution

External body features of newborn <i>S. crassicaudata</i>.

<p>Microphotograph of a stage 18 newborn dunnart as seen from the right and from the front. Note the prominent orofacial features, including fused mandible (Mb), and wide nostrils (N). The eyes (Ey) are small and lightly pigmented. Forelimbs are more advanced than hindlimbs, with digits serrated as compared to completely fused. Scale bar: 1mm.</p

Craniofacial features of stages 19–21 <i>S</i>. <i>crassicaudata</i>.

<p>Haematoxylin/eosin staining through rostral (left) and caudal (right) regions of the head of <i>S</i>. <i>crassicaudata</i> at stages 19 (A), 20 (B), and 21 (C) in the coronal plane (postnatal days 4–7, 8–11, and 12–15, respectively). Insets of the developing eye at corresponding ages (D-F, respectively). ac, anterior commissure; BG, basal ganglia; Cg, cingulate cortex; Cla, claustrum; Co, cornea; CP, cortical plate; ec, external capsule; En, endopiriform nucleus; Ey, eye; Et, ethmoid bone; F, follicle; Ga, ganglion layer; GE, ganglionic eminence; Hp, hippocampus; ic, internal capsule; IG, indusium griseum; L, lens; LE, lens epithelium; LF, lens fibres; Li, eyelid; lot, lateral olfactory tract; LV, lateral ventricle; LVe, lens vesicle; Mb, mandibulary process; Mo, mouth; Mx, maxillary process; MZ, marginal zone; NC, nasal cavity; Nb, neuroblastic layer; OE, olfactory neuroepithelium; ON, optic nerve; Orb, orbital bone; OS, optic stalk; OT, olfactory tubercle; Pi, pigment epithelium; Pir, piriform cortex; PoA, preoptic area; Pp, preplate; PSp; presphenoid bone; Re, retinal layer; Se, septum; Sp, subplate; St, striatum; SVZ, subventricular zone; T, tongue; VZ, ventricular zone. Scale bars: 500 μm (A-C), 100 μm (E-F).</p

Developmental growth curves of postnatal <i>S</i>. <i>crassicaudata</i>.

<p>Semilogarithmic relationships between the postnatal age (in days) and crown-rump length (A), head width (B), forelimb length (C), and hindlimb length (D). Mean ± standard error of the mean, as well as best-fit regression curves (red lines) and 95% confidence intervals (dotted lines) are indicated in each case. Non-linear functions whereby <i>y</i> indicates the corresponding measurements (in mm) and <i>x</i> the age in days, as well as <i>R</i>^<i>2</i> values are indicated. See Tables <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0184450#pone.0184450.t001" target="_blank">1</a> and <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0184450#pone.0184450.t002" target="_blank">2</a> for additional information.</p

Developmental series of postnatal <i>S</i>. <i>crassicaudata</i>.

<p>A system of twenty-nine arbitrary stages from conception to weaning is included to match equivalent stages in human (Carnegie staging system) and mouse (Thieler staging system). Birth occurs at stage 18. Corresponding age of each stage is included as a range of postnatal days (P). See <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0184450#pone.0184450.t003" target="_blank">Table 3</a> for further details. Scale bar: 5 mm.</p

Craniofacial features of newborn <i>S</i>. <i>crassicaudata</i>.

<p>(A) Schematic of a stage 18 dunnart head (postnatal day 0–3) indicating the relative size and position of nostrils, mouth, tongue, eyes and brain, as well as the section planes shown in (B-D). (B-D) Haematoxylin/eosin staining of a rostral-caudal series through the planes depicted in panel A reveals orofacial, sensory and brain structures of newborn dunnarts, including a prominent tongue (T) that encloses the teat inside the mouth (Mo) reaching the lateral margins of the palate (Pal). Large nasal cavities (NC) with fused palate (Pal) and nasal septum (NSe) can be seen, including condensation of mandibular (Mb) and maxillary (Mx) processes, eyes (Ey) fully covered by skin, and scattered vibrissal follicles (VF) in the snout. Telencephalic structures include the olfactory bulb (OB), with surrounding olfactory nerve layer (onl), preplate (Pp), ventricular zone (VZ) and ganglionic eminences (GE) as well as a large lateral ventricle (LV). E-F, inset of the regions highlighted in B-D depicting developing sensory structures. E, the vomeronasal organ (VO) includes a lumen (VLu), neuroepithelium (VE) and capsule (VC) at the base of NSe and Pal. F, a thick olfactory neuroepithelium (OE) is located at the roof of the NC, immediately below the presumptive cribiform plate (CrP). G, eye development has just undergone closure of the lens vesicle (LVe), the pigment epithelium (Pi) outlines a dark ring around cells of the retina (Re). Et, ethmoid bone; Orb, orbital bone; PoA, preoptic area; PSp; presphenoid bone. Scale bar: 500 μm.</p