Polygenicity in a box: Copy number variants, neural circuit development, and neurodevelopmental disorders.

Clinically defined neurodevelopmental disorders (cd-NDDs), including Autistic Spectrum Disorder (ASD) and Schizophrenia (Scz), are primarily polygenic: Multiple risk genes distributed across the genome, in potentially infinite combinations, account for variable pathology. Polygenicity raises a fundamental question: Can "core" cd-NDD pathogenic mechanisms be identified given this genomic complexity? With the right models and analytic targets, a distinct class of polygenic mutations-Copy Number Variants (CNVs): contiguous gene deletions or duplications associated with cd-NDD risk-provide a singular opportunity to define cd-NDD pathology. CNVs orthologous to those that confer cd-NDD risk have been engineered in animals as well as human stem cells.

Out of Line or Altered States? Neural Progenitors as a Target in a Polygenic Neurodevelopmental Disorder.

The genesis of a mature complement of neurons is thought to require, at least in part, precursor cell lineages in which neural progenitors have distinct identities recognized by exclusive expression of one or a few molecular markers. Nevertheless, limited progenitor types distinguished by specific markers and lineal progression through such subclasses cannot easily yield the magnitude of neuronal diversity in most regions of the nervous system. The late Verne Caviness, to whom this edition of Developmental Neuroscience is dedicated, recognized this mismatch.

Ranbp1 modulates morphogenesis of the craniofacial midline in mouse models of 22q11.2 deletion syndrome.

Facial dysmorphology is a hallmark of 22q11.2 deletion syndrome (22q11DS). Nearly all affected individuals have facial features characteristic of the syndrome: a vertically long face with broad nasal bridge, narrow palpebral fissures and mild micrognathia, sometimes accompanied by facial skeletal and oropharyngeal anomalies.

Selective disruption of trigeminal sensory neurogenesis and differentiation in a mouse model of 22q11.2 deletion syndrome.

22q11.2 Deletion Syndrome (22q11DS) is a neurodevelopmental disorder associated with cranial nerve anomalies and disordered oropharyngeal function, including pediatric dysphagia. Using the LgDel 22q11DS mouse model, we investigated whether sensory neuron differentiation in the trigeminal ganglion (CNgV), which is essential for normal orofacial function, is disrupted.

Why Does the Face Predict the Brain? Neural Crest Induction, Craniofacial Morphogenesis, and Neural Circuit Development.

Mesenchephalic and rhombencephalic neural crest cells generate the craniofacial skeleton, special sensory organs, and subsets of cranial sensory receptor neurons. They do so while preserving the anterior-posterior (A-P) identity of their neural tube origins. This organizational principle is paralleled by central nervous system circuits that receive and process information from facial structures whose A-P identity is in register with that in the brain.

Disrupted Coordination of Hypoglossal Motor Control in a Mouse Model of Pediatric Dysphagia in DiGeorge/22q11.2 Deletion Syndrome.

We asked whether the physiological and morphologic properties of hypoglossal motor neurons (CNXII MNs) that innervate protruder or retractor tongue muscles are disrupted in neonatal mice that carry a heterozygous deletion parallel to that associated with DiGeorge/22q11.2 deletion syndrome (22q11.2DS).

Persistent Feeding and Swallowing Deficits in a Mouse Model of 22q11.2 Deletion Syndrome.

Disrupted development of oropharyngeal structures as well as cranial nerve and brainstem circuits may lead to feeding and swallowing difficulties in children with 22q11. 2 deletion syndrome (22q11DS). We previously demonstrated aspiration-based dysphagia during early postnatal life in the mouse model of 22q11DS along with disrupted oropharyngeal morphogenesis and divergent differentiation and function of cranial motor and sensory nerves.

In the line-up: deleted genes associated with DiGeorge/22q11.2 deletion syndrome: are they all suspects?

Background: 22q11.2 deletion syndrome (22q11DS), a copy number variation (CNV) disorder, occurs in approximately 1:4000 live births due to a heterozygous microdeletion at position 11.2 (proximal) on the q arm of human chromosome 22 (hChr22) (McDonald-McGinn and Sullivan, Medicine 90:1-18, 2011).

Mitochondrial Dysfunction Leads to Cortical Under-Connectivity and Cognitive Impairment.

Under-connectivity between cerebral cortical association areas may underlie cognitive deficits in neurodevelopmental disorders, including the 22q11.2 deletion syndrome (22q11DS). Using the LgDel 22q11DS mouse model, we assessed cellular, molecular, and developmental origins of under-connectivity and its consequences for cognitive function.

The strengths of the genetic approach to understanding neural systems development and function: Ray Guillery's synthesis.

The organization and function of sensory systems, especially the mammalian visual system, has been the focus of philosophers and scientists for centuries-from Descartes and Newton onward. Nevertheless, the utility of understanding development and its genetic foundations for deeper insight into neural function has been debated: Do you need to know how something is assembled-a car, for example-to understand how it works or how to use it-to turn on the ignition and drive? This review addresses this issue for sensory pathways. The pioneering work of the late Rainer W.

Altered neurobiological function of brainstem hypoglossal neurons in DiGeorge/22q11.2 Deletion Syndrome.

DiGeorge/22q11.2 Deletion Syndrome (22q11DS) is a common genetic microdeletion syndrome that underlies several neurodevelopmental disorders including autism, attention deficit/hyperactivity disorder, and schizophrenia. In addition to cognitive impairments, those with 22q11DS have disrupted feeding and swallowing from birth onward.

Hard to swallow: Developmental biological insights into pediatric dysphagia.

Pediatric dysphagia-feeding and swallowing difficulties that begin at birth, last throughout childhood, and continue into maturity--is one of the most common, least understood complications in children with developmental disorders. We argue that a major cause of pediatric dysphagia is altered hindbrain patterning during pre-natal development. Such changes can compromise craniofacial structures including oropharyngeal muscles and skeletal elements as well as motor and sensory circuits necessary for normal feeding and swallowing.

Transcriptional regulation of cranial sensory placode development.

Cranial sensory placodes derive from discrete patches of the head ectoderm and give rise to numerous sensory structures. During gastrulation, a specialized "neural border zone" forms around the neural plate in response to interactions between the neural and nonneural ectoderm and signals from adjacent mesodermal and/or endodermal tissues. This zone subsequently gives rise to two distinct precursor populations of the peripheral nervous system: the neural crest and the preplacodal ectoderm (PPE).

Ranbp1, Deleted in DiGeorge/22q11.2 Deletion Syndrome, is a Microcephaly Gene That Selectively Disrupts Layer 2/3 Cortical Projection Neuron Generation.

Ranbp1, a Ran GTPase-binding protein implicated in nuclear/cytoplasmic trafficking, is included within the DiGeorge/22q11.2 Deletion Syndrome (22q11.2 DS) critical region associated with behavioral impairments including autism and schizophrenia.

On becoming neural: what the embryo can tell us about differentiating neural stem cells.

THE EARLIEST STEPS OF EMBRYONIC NEURAL DEVELOPMENT ARE ORCHESTRATED BY SETS OF TRANSCRIPTION FACTORS THAT CONTROL AT LEAST THREE PROCESSES: the maintenance of proliferative, pluripotent precursors that expand the neural ectoderm; their transition to neurally committed stem cells comprising the neural plate; and the onset of differentiation of neural progenitors. The transition from one step to the next requires the sequential activation of each gene set and then its down-regulation at the correct developmental times. Herein, we review how these gene sets interact in a transcriptional network to regulate these early steps in neural development.

Cxcr4 regulation of interneuron migration is disrupted in 22q11.2 deletion syndrome.

Interneurons are thought to be a primary pathogenic target for several behavioral disorders that arise during development, including schizophrenia and autism. It is not known, however, whether genetic lesions associated with these diseases disrupt established molecular mechanisms of interneuron development. We found that diminished 22q11.

22q11 Gene dosage establishes an adaptive range for sonic hedgehog and retinoic acid signaling during early development.

We asked whether key morphogenetic signaling pathways interact with 22q11 gene dosage to modulate the severity of cranial or cardiac anomalies in DiGeorge/22q1 deletion syndrome (22q11DS). Sonic hedgehog (Shh) and retinoic acid (RA) signaling is altered in the brain and heart-clinically significant 22q11DS phenotypic sites-in LgDel mouse embryos, an established 22q11DS model. LgDel embryos treated with cyclopamine, an Shh inhibitor, or carrying mutations in Gli3(Xtj), an Shh-signaling effector, have morphogenetic anomalies that are either not seen, or seen at significantly lower frequencies in control or single-mutant embryos.

Proliferative and transcriptional identity of distinct classes of neural precursors in the mammalian olfactory epithelium.

Neural precursors in the developing olfactory epithelium (OE) give rise to three major neuronal classes - olfactory receptor (ORNs), vomeronasal (VRNs) and gonadotropin releasing hormone (GnRH) neurons. Nevertheless, the molecular and proliferative identities of these precursors are largely unknown. We characterized two precursor classes in the olfactory epithelium (OE) shortly after it becomes a distinct tissue at midgestation in the mouse: slowly dividing self-renewing precursors that express Meis1/2 at high levels, and rapidly dividing neurogenic precursors that express high levels of Sox2 and Ascl1.

Developmental and degenerative features in a complicated spastic paraplegia.

Objective: We sought to explore the genetic and molecular causes of Troyer syndrome, one of several complicated hereditary spastic paraplegias (HSPs). Troyer syndrome had been thought to be restricted to the Amish; however, we identified 2 Omani families with HSP, short stature, dysarthria and developmental delay-core features of Troyer syndrome-and a novel mutation in the SPG20 gene, which is also mutated in the Amish. In addition, we analyzed SPG20 expression throughout development to infer how disruption of this gene might generate the constellation of developmental and degenerative Troyer syndrome phenotypes.

Diminished dosage of 22q11 genes disrupts neurogenesis and cortical development in a mouse model of 22q11 deletion/DiGeorge syndrome.

The 22q11 deletion (or DiGeorge) syndrome (22q11DS), the result of a 1.5- to 3-megabase hemizygous deletion on human chromosome 22, results in dramatically increased susceptibility for "diseases of cortical connectivity" thought to arise during development, including schizophrenia and autism. We show that diminished dosage of the genes deleted in the 1.

Molecular specification and patterning of progenitor cells in the lateral and medial ganglionic eminences.

We characterized intrinsic and extrinsic specification of progenitors in the lateral and medial ganglionic eminences (LGE and MGE). We identified seven genes whose expression is enriched or restricted in either the LGE [biregional cell adhesion molecule-related/downregulated by oncogenes binding protein (Boc), Frizzled homolog 8 (Fzd8), Ankrd43 (ankyrin repeat domain-containing protein 43), and Ikzf1 (Ikaros family zinc finger 1)] or MGE [Map3k12 binding inhibitory protein 1 (Mbip); zinc-finger, SWIM domain containing 5 (Zswim5); and Adamts5 [a disintegrin-like and metallopeptidase (reprolysin type) with thrombospondin type 1 motif, 5]]. Boc, Fzd8, Mbip, and Zswim5 are apparently expressed in LGE or MGE progenitors, whereas the remaining three are seen in the postmitotic mantle zone.

No evidence for parental imprinting of mouse 22q11 gene orthologs.

Non-Mendelian factors may influence central nervous system (CNS) phenotypes in patients with 22q11 Deletion Syndrome (22q11DS, also known as DiGeorge or Velocardiofacial Syndrome), and similar mechanisms may operate in mice carrying a deletion of one or more 22q11 gene orthologs. Accordingly, we examined the influence of parent of origin on expression of 25 murine 22q11 orthologs in the developing and mature CNS using single nucleotide polymorphism (SNP)-based analysis in interspecific crosses and quantification of mRNA in a murine model of 22q11DS. We found no evidence for absolute genomic imprinting or silencing.

Position and time specify the migration of a pioneering population of olfactory bulb interneurons.

We defined the cellular mechanisms for genesis, migration, and differentiation of the initial population of olfactory bulb (OB) interneurons. This cohort of early generated cells, many of which become postmitotic on embryonic day (E) 14.5, differentiates into a wide range of mature OB interneurons by postnatal day (P) 21, and a substantial number remains in the OB at P60.

Noses and neurons: induction, morphogenesis, and neuronal differentiation in the peripheral olfactory pathway.

Non-axial mesenchymal/epithelial (M/E) induction guides peripheral olfactory pathway differentiation using cellular and molecular mechanisms similar to those in the developing limbs, aortic arches, and branchial arches. At each of these bilaterally symmetric sites off the midline axis, a thickened ectodermal epithelium is apposed to a specialized mesenchyme derived largely, but not exclusively, from the neural crest. The capacity of M/E interaction in the olfactory primordia (the combined olfactory placodal epithelium and adjacent mesenchyme) to induce a distinct class of sensory receptor neurons-olfactory receptor neurons-suggests that this mechanism has been modified to accommodate neurogenesis, neurite outgrowth, and axon guidance, in addition to musculoskeletal differentiation, chondrogenesis, and vasculogenesis.

Retinoic acid signaling identifies a distinct precursor population in the developing and adult forebrain.

We asked whether retinoic acid (RA), an established transcriptional regulator in regenerating and developing tissues, acts directly on distinct cell classes in the mature or embryonic forebrain. We identified a subset of slowly dividing precursors in the adult subventricular zone (SVZ) that is transcriptionally activated by RA. Most of these cells express glial fibrillary acidic protein, a smaller subset expresses the epidermal growth factor receptor, a few are terminal deoxynucleotidyl transferase-mediated biotinylated UTP nick end labeling positive, and they can be mitotically labeled by sustained rather than acute bromodeoxyuridine exposure.