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Math1 Is Essential for Genesis of Cerebellar Granule Neurons

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Math1 Is Essential for Genesis of Cerebellar Granule Neurons letters to nature Received 5 June; accepted 18 August 1997. gene to be shown to be required in vivo for the genesis of granule 1. Lebacq-Verheyden, A.-M., Trepel, J., Sausville, E. A. & Battey, J. in Handbook of Experimental cells, and hence the predominant neuronal population in the Pharmacology, Vol. 95/II. Peptide Growth Factors and their Receptors II (eds Sporn, M. B. & Roberts, A. B.) 71–124 (Springer, Berlin, Heidelberg, 1990). cerebellum. 2. Spindel, E. R., Giladi, E., Brehm, P., Goodman, R. H. & Segerson, T. P. Cloning and functional The mammalian cerebellum consists of deep centrally located characterization of a complementary DNA encoding the murine fibroblast bombesin/gastrin- neurons, referred to as the deep nuclei, and a peripheral cortex. The releasing peptide receptor. Mol. Endocrinol. 4, 1956–1963 (1990). 3. Battey, J. F. et al. Molecular cloning of the bombesin/gastrin-releasing peptide receptor from Swiss 3T3 cortex contains two principal neuronal subtypes, the Purkinje cells cells. Proc. Natl Acad. Sci. USA 88, 395–399 (1991). and the cells of the internal granular layer (IGL). The IGL neurons, 4. Corjay, M. H. et al. Two distinct bombesin receptor subtypes are expressed and functional in human lung carcinoma cells. J. Biol. Chem. 266, 18771–18779 (1991). which eventually constitute most of the neurons in the cerebellum, 5. Wada, E. et al. cDNA cloning, characterization, and brain region-specific expression of a neuromedin- are derived from peripherally located cells in the external germinal B-preferring bombesin receptor. Neuron 6, 421–430 (1991). layer (EGL) which migrate postnatally along radial glia1,5. The 6. Fathi, Z. et al. A novel bombesin receptor subtype selectively expressed in testis and lung carcinoma cells. J. Biol. Chem. 268, 5979–5984 (1993). mouse cerebellar anlage is specified at embryonic-day 9 (E9) just 7. Gorbulev, V., Akhundova, A., Buchner, H. & Fahrenholz, F. Molecular cloning of a new bombesin anterior to the area where closure of the neural tube is incomplete. receptor subtype expressed in uterus during pregnancy. Eur. J. Biochem. 208, 405–410 (1992). 8. Ohki-Hamazaki, H., Wada, E., Matsui, K. & Wada, K. Cloning and expression of the neuromedin B The neuroepithelium of the ventricular zone in the metencephalon receptor and the third subtype of bombesin receptor genes in the mouse. Brain Res. 762, 165–172 gives rise to the precursors of the neurons of the deep nuclei and (1997). Purkinje cells6. The precursors of the EGL are derived at E13–E15 9. Bray, G. A. & York, D. A. Hypothalamic and genetic obesity in experimental animals: An autonomic and endocrine hypothesis. Physiol. Rev. 59, 719–809 (1979). from a structure named the rhombic lip (also known as the germinal 10. Frederich, R. C. et al. Leptin levels reflect body lipid content in mice: Evidence for diet-induced trigone), which is located at the posterior edge of the cerebellar resistance to leptin action. Nature Med. 1, 1311–1314 (1995). 1,5,7 11. Maffei, M. et al. Leptin levels in human and rodent: Measurement of plasma leptin and ob RNA in anlage (Fig. 1). The proliferating cells of the rhombic lip, which obese and weight-reduced subjects. Nature Med. 1, 1155–1161 (1995). are committed to become EGL neurons, disperse rostrally over the 12. Schwartz, M. W., Peskind, E., Raskind, M., Boyko, E. J. & Porte, D. Jr Cerebrospinal fluid leptin levels: surface of the cerebellar anlage, where they establish the EGL. Relationship to plasma levels and to adiposity in humans. Nature Med. 2, 589–593 (1996). 13. Wu, J. M., Nitecki, D. E., Biancalana, S. & Feldman, R. I. Discovery of high affinity bombesin receptor Proliferation of these granule cell precursors continues in the EGL subtype 3 agonists. Mol. Pharmacol. 50, 1355–1363 (1996). until postnatal day 15 (P15). The EGL cells migrate inwardly to give 14. Boer, P.H. et al. Polymorphisms in the coding and noncoding region of murine Pgk-1 alleles. Biochem. Gen. 28, 299–308 (1990). rise to the IGL, starting at birth until day P20, when maturation of 1,5,7 15. Yanofsky, R. L., Fine, M. & Pellow, J. W. A mutant neomycin phosphotransferase II gene reduces the the cerebellum is complete . resistance of transformants to antibiotic selection pressure. Proc. Natl Acad. Sci. USA 87, 3435–3439 The Drosophila atonal gene is essential for the generation of the (1990). 16. Nabeshima, Y. et al. Myogenin gene disruption results in perinatal lethality because of severe muscle chordotonal organs, the proprioreceptors, and the R8 photorecep- defect. Nature 364, 532–535 (1993). tor precursors in the eye4,8. Adult flies that lack atonal function do 17. Hooper, M., Hardy, K., Handyside, A., Hunter, S. & Monk, M. HPRT-deficient (Lesch–Nyhan) mouse 8 embryos derived from germline colonization by cultured cells. Nature 326, 292–295 (1987). not have photoreceptors, are uncoordinated and tend not to fly . 18. Yamamoto, K. & Kikuyama, S. Radioimmunoassay of prolactin in plasma of bullfrog tadpoles. Expression of Math1, the mouse atonal homologue, is highly Endocrinol. Jpn 29, 159–167 (1982). restricted to a few neurons in the hindbrain and dorsal neural 19. Bouillaud, F., Weissenbach, J. & Ricquier, D. Complete cDNA-derived amino acid sequence of rat 2,3 brown fat uncoupling protein. J. Biol. Chem. 261, 1487–1490 (1986). tube . Math1 is expressed in the precursors of the EGL in the Acknowledgements. We thank J.-I. Miyazaki for ES cells and training regarding ES cells; A. F. Parlow for rhombic lip starting at E13, and later in the EGL of the developing mouse growth hormone and polyclonal monkey anti-rat GH serum; K. Wakabayashi for goat anti- cerebellum (Fig. 1). Math1 expression ceases during the inward monkey IgG serum; H. Ohno for rat UCP1 probe; T. Nishikawa for providing Animex Auto; N. M. Le Douarin, K. Mikoshiba, R. S. Petralia and J. Smith for critical reading of the manuscript. This work was migration phase of the granule cells to the IGL. To investigate the supported in part by research grants from the Ministry of Education, Science, Sports and Culture, the role of Math1 in cerebellar development, a targeted deletion of the Ministry of Health and Welfare, the Science and Technology Agency of Japan, the Japan Health Science m1 Foundation. Math1 gene (Math1 ) was generated by using embryonic stem (ES) cell technology (Fig. 2a). Heterozygous mice were intercrossed to Correspondence and requests for materials should be addressed to H.O.-H. (e-mail: [email protected]) or K.W. (e-mail: [email protected]). obtain mice homozygous for the Math1 deletion (Fig. 2b). Absence of a hybridization signal with DNA from homozygous mutant mice, when probed with an internal probe spanning the basic-helix– Math1 is essential for genesis ab AQ of cerebellar granule neurons MC SC Nissim Ben-Arie*†, Hugo J. Bellen*‡k, Dawna L. Armstrong§, IV Alanna E. McCall†, Polina R. Gordadze†, Qiuxia Guo§, Martin M. Matzuk*‡§ & Huda Y. Zoghbi*† k IC Cb IST Cb EGL Departments of *Molecular and Human Genetics, †Pediatrics, ‡Cell Biology, NE NE CP EGL §Pathology, and kHoward Hughes Medical Institute, Baylor College of Medicine, IV URL/GT URL/GT Houston, Texas 77030, USA PO LRL CP ......................................................................................................................... MO The cerebellum is essential for fine motor control of movement and posture, and its dysfunction disrupts balance and impairs IO control of speech, limb and eye movements. The developing cerebellum consists mainly of three types of neuronal cells: Figure 1 The developing cerebellum at E16.5. The sagittal (a) and coronal (b) granule cells in the external germinal layer, Purkinje cells, and views show the localization of the cerebellum (Cb) between the inferior colliculus neurons of the deep nuclei1. The molecular mechanisms that (IC), pons (PO), mesencephalon (MC) and medulla oblongata (MO). The germinal underlie the specific determination and the differentiation of matrix, which gives rise to EGL precursors, is the rhombic lip, with an upper and a each of these neuronal subtypes are unknown. Math1 (refs 2, 3), lower component (URL, LRL, respectively). The proliferative zone at the URL, the the mouse homologue of the Drosophila gene atonal 4, encodes a germinal trigone (GT), has three prongs: EGL, neuroepithelium (NE), and choroid basic helix–loop–helix transcription factor that is specifically plexus (CP). Granule cell precursors originate at the URL/GTand migrate (arrow) expressed in the precursors of the external germinal layer and to form the EGL. The LRL will contribute to the medullar precerebellar nuclei, their derivatives. Here we report that mice lacking Math1 fail to including the inferior olive (IO). Math1 is expressed in granule precursors in GT form granule cells and are born with a cerebellum that is devoid of and in emerging EGL (shaded area). AQ, aqueduct of Sylvius; IST, isthmus; IV, an external germinal layer. To our knowledge, Math1 is the first fourth ventricle; SC, superior colliculus. Adapted from ref.1. Nature © Macmillan Publishers Ltd 1997 NATURE | VOL 390 | 13 NOVEMBER 1997 169 letters to nature loop–helix (bHLH) domain, confirmed that the mutation is a null a allele (data not shown). A H RI RV H A A X A RI Mice heterozygous for the Math1 deletion are viable, fertile and Math1 locus appear normal. Genotyping of newborn mice from heterozygous intercrosses demonstrated that the targeted allele did not result in RI RV X A embryonic lethality. The observed ratio of genotypes fitted that RI H PGKhprt MC1-TK expected for a fully penetrant, mendelian recessive inheritance Targeting pattern, with 28 (25.2%) wild types, 55 heterozygote (49.5%) and B BN N vector 28 (25.2%) homozygote (null) mice. Math1-null mice are born A H RI RV X A RI alive, but fail to breathe, become cyanotic, and die a few minutes RI H Targeted PGKhprt after birth.
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