Int. J. Devl Neuroscience 31 (2013) 138–144 Contents lists available at SciVerse ScienceDirect International Journal of Developmental Neuroscience j o ur nal homep age : www.elsevier.com/locate/ ijdevneu Morphology of the facial motor nuclei in a rat model of autism during early development Akiko Oyabu, Yasura Tashiro ∗ , Takahiro Oyama, Kensaku Ujihara, Takeshi Ohkawara, Michiru Ida-Eto, Masaaki Narita Department of Anatomy II, Graduate School of Medicine, Mie University, Japan a r t i c l e i n f o Article history: Received 9 October 2012 Received in revised form 22 November 2012 Accepted 8 December 2012 Keywords: Cranial motor nuclei Migration Autism Hindbrain Rat embryo a b s t r a c t The development of facial nuclei in animal models of disease is poorly understood, but autism is some- times associated with facial palsy. In the present study, to investigate migration of facial neurons and initial facial nucleus formation in an animal model of autism, rat embryos were treated with valproic acid (VPA) in utero at embryonic day (E) 9.5 and their facial nuclei were analyzed by in situ hybridization at E13.5, E14.5 and E15.5. Signals for Tbx20, which is expressed in early motor neurons, appeared near the floor plate at the level of the vestibular ganglion and extended caudolaterally, where they became ovoid in shape. This pattern of development was similar between control and VPA-exposed embryos. However, measurements of the migratory pathway and the size of the facial nuclei revealed that exposure to VPA hindered the caudal migration of neurons to the facial nuclei. Signals for cadherin 8, which is expressed in mature facial nuclei, revealed that exposure to VPA caused a significant reduction in the size of the facial nuclei. Our findings provide the first quantitative description of tangential migration and nucleus formation in the developing hindbrain in a rat model of autism. © 2012 ISDN. Published by Elsevier Ltd. All rights reserved. 1. Introduction Neural migration is one of the pivotal first steps in precisely establishing the neural network, and both radial and tangential migrations contribute to the organization of the cortex into layers and nucleus formation in the developing brain. Numerous recent studies comparing the time courses of neural migration in wild- type and transgenic animals have revealed that a combination of molecules regulates the direction of neural migration (Bloch- Gallego et al., 2005; Chédotal and Rijli, 2009; Chédotal, 2010; Hatten, 1999; Huang, 2009). Developing facial nuclei migrate tangentially within the hind- brain. During early development, neurons that will eventually form the facial nuclei are generated in rhombomere 4 (r4) then migrate caudally to r6 to the site of the facial nuclei (Chandrasekhar, 2004; Hatten, 1999; Noden, 1993; Yamamoto and Schwarting, 1991). Studies using transgenic mice, both in vivo and in vitro with cells derived from these mice, have identified some of the molecules that are responsible for regulating tangential migration (Chédotal and Rijli, 2009; Huang, 2009). However, the development and migration ∗ Corresponding author at: Department of Anatomy II, Graduate School of Medicine, Mie University, 2-174 Edobashi, Tsu, Mie 514-8507, Japan. Tel.: +81 59 231 9938; fax: +81 59 231 9938. E-mail address: ytashiro@doc.medic.mie-u.ac.jp (Y. Tashiro). of neurons to the facial nuclei are poorly understood in animal models of disease. Autism spectrum disorders (ASDs) are neurodevelopmental dis- orders characterized by impairments in social interaction and communication, and are associated with repetitive behaviors and interests (Charman and Baird, 2002; Filipek et al., 1999). An associ- ation of autism with facial nerve (7th cranial nerve) palsy has been described in several cases of thalidomide embryopathy, Möbius sequence, CHARGE association and Goldenhar syndrome (Gillberg and Winnergård, 1984; Miller et al., 2005; Ornitz et al., 1977). Given this association, a more precise understanding of the devel- opment of the facial nuclei, from which facial nerves originate, in ASD patients, could potentially be indispensable for elucidating the pathogenesis of autism with facial palsy. Rodent models of autism have been particularly useful for elu- cidating the association of autism with embryonic development of the nervous system. Epidemiological studies had revealed that exposure to thalidomide (THAL) or valproic acid (VPA) during the first trimester of pregnancy causes a higher incidence of autism in human offspring (Strömland et al., 1994; Williams et al., 2001); based on this, a rat model of autism was generated by prenatal THAL or VPA exposure (Narita et al., 2002). In studies using this model, behavioral, biochemical and neuroanatomic similarities between human cases of autism and rats exposed to VPA in utero were observed (Ingram et al., 2000; Miyazaki et al., 2005; Narita Naoko et al., 2002; Narita Masaaki et al., 2010; Rodier et al., 1996, 1997). 0736-5748/$36.00 © 2012 ISDN. Published by Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.ijdevneu.2012.12.002