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. 2000 Sep 1;14(17):2134-9.
doi: 10.1101/gad.820400.

Ventral neural patterning by Nkx homeobox genes: Nkx6.1 controls somatic motor neuron and ventral interneuron fates

M Sander  1 , S Paydar, J Ericson, J Briscoe, E Berber, M German, T M Jessell, J L Rubenstein
Affiliations

Ventral neural patterning by Nkx homeobox genes: Nkx6.1 controls somatic motor neuron and ventral interneuron fates

M Sander et al. Genes Dev. .

Abstract

There is growing evidence that sonic hedgehog (Shh) signaling regulates ventral neuronal fate in the vertebrate central nervous system through Nkx-class homeodomain proteins. We have examined the patterns of neurogenesis in mice carrying a targeted mutation in Nkx6.1. These mutants show a dorsal-to-ventral switch in the identity of progenitors and in the fate of postmitotic neurons. At many axial levels there is a complete block in the generation of V2 interneurons and motor neurons and a compensatory ventral expansion in the domain of generation of V1 neurons, demonstrating the essential functions of Nkx6.1 in regional patterning and neuronal fate determination.

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Figures

Figure 1
Figure 1
Selective changes in homeobox gene expression in ventral progenitor cells in Nkx6.1 mutant embryos. Expression of Nkx6.1 in transverse sections of the ventral neural tube at E9.5 (A), E10.5 (B), or E12.5 (C). Summary diagrams showing domains of homeobox gene expression in wild-type mouse embryos (D) and the change in pattern of expression of these genes in Nkx6.1 mutants (E), based on analyses at E10.0–12.5. Expression of Nkx6.1 (F,J), Dbx2 (G,H,K,L), and Gsh1 (I,M) in the caudal neural tube of wild-type (F–I) and Nkx6.1 mutant (J–M) embryos. Horizontal lines, approximate position of dorsoventral boundary of the neural tube; vertical lines, expression levels of Dbx2 and Gsh1. Expression of Shh (N,R), Pax7 (N,R), Nkx2.2 (O,S), Pax6 (P,S), Dbx1 (P,T), and Nkx2.9 (Q,U) in wild-type (N–Q) or Nkx6–1 mutant (R–U) embryos at spinal (N–P,R–T) and caudal hindbrain (Q,U) levels. Arrowheads, approximate position of the dorsal limit of Nkx6.1 expression. Scale bar shown in J = 100 μm (A–C), 50 μm (F–M), or 60 μm (N–U).
Figure 2
Figure 2
Disruption of motor neuron differentiation in Nkx6.1 mutant embryos. The relationship between the domain of Nkx6.1 expression (A–C, green) by ventral progenitors and the position of generation of motor neurons and V2 interneurons (A–D, red) in the ventral spinal cord of E10.5 wild-type embryos. (A) Isl1/2 motor neurons; (B) HB9 motor neurons; (C) Lhx3 (Lim3) expression (red) by motor neurons, V2 interneurons, and their progenitors is confined to the Nkx6.1 progenitor domain. (D) Chx10 (green) V2 interneurons coexpress Lhx3 (red). Expression of Isl1/2 (E,I), HB9 (F,J), Lhx3 (G,K), and Phox2a/b (H,L) in the ventral spinal cord (E,F,G) and caudal hindbrain (H) of E10.5 wild-type (E–H) and Nkx6.1 mutant (I–L) embryos. Pattern of expression of Isl1/2 and Lhx3 at cervical (M,N,Q,R) and thoracic (O,P,S,T) levels of E12.5 wild-type (M–P) and Nkx6.1 mutant (Q–T) embryos. Arrows, position of Isl1 dorsal D2 interneurons. Scale bar shown in I = 60 μm (A–D), 80 μm (E–L), or 120 μm (M–T).
Figure 3
Figure 3
Motor neuron subtype differentiation in Nkx6.1 mutant mice. Depletion of both median (MMC) and lateral (LMC) motor column neurons in Nkx6.1 mutant mice. Expression of Isl1/2 (red) and Lhx3 (green) in E12.5 wild-type (A,C) and Nkx6.1 mutant (B,D) mice spinal cord at forelimb levels. (E–J) Motor neuron generation at caudal hindbrain level. (E,F) Nkx6.1 expression in progenitor cells and visceral motor neurons in the caudal hindbrain (rhombomere [r] 7/8) of E10.5–E11 wild-type (E) Nkx6.1 mutant (F) mice. HB9 expression in hypoglossal motor neurons in E10.5–E11 wild-type (G) and Nkx6.1 mutant (H) mice. Coexpression of Isl1 (green) and Phox2a/b (red) in wild-type (I) or Nkx6.1 mutant (J) mice. (h) hypoglossal motor neurons; (v) visceral vagal motor neurons. Scale bar shown in C = 50 μm (A–D) or 70 μm (E–J).
Figure 4
Figure 4
A switch in ventral interneuron fates in Nkx6.1 mutant mice. Chx10 expression in V2 neurons at rostral cervical levels of E10.5 wild-type (A) and Nkx6.1 mutant (B) embryos. En1 expression by V1 neurons at rostral cervical levels of wild-type (C) and Nkx6.1 mutant (D) embryos. Pax2 expression in a set of interneurons that includes V1 neurons (Burrill et al. 1997) at caudal hindbrain levels of wild-type (E) and Nkx6.1 mutant (F) embryos. (G,H) Sim1 expression by V3 neurons in the cervical spinal cord of wild-type (G) and Nkx6.1 mutant (H) embryos. Evx1 expression by V0 neurons at caudal hindbrain levels of wild-type (I) and Nkx6.1 mutant (J) embryos. En1 (red) and Lhx3 (green) expression by separate cell populations in the ventral spinal cord of E11 wild-type (K) and Nkx6.1 mutant (L) embryos. Scale bar shown in B = 60 μm (A–D), 75 μm (E,F), 70 μm (G,J,H,J), or 35μ m (K,L).
Figure 5
Figure 5
Changes in progenitor domain identity and neuronal fate in the spinal cord of Nkx6.1 mutant embryos. (A) In wild-type mouse embryos, cells in the Nkx6.1 progenitor domain give rise to three classes of ventral neurons: V2, motor (MN), and V3 neurons. V3 neurons derive from cells in the ventral most region of Nkx6.1 expression that also express Nkx2.2 and Nkx2.9. V1 neurons derive from progenitor cells that express Dbx2 but not Nkx6.1. (B). In Nkx6.1 mutant embryos the domain of Dbx2 expression by progenitor cells expands ventrally and by embryonic day 12 (E12) occupies the entire dorsoventral extent of the ventral neural tube, excluding the floor plate. Checked blue indicates the gradual onset of ventral Dbx2 expression. This ventral shift in Dbx2 expression is associated with a marked decrease in the generation of V2 and MN neurons and a ventral expansion in the domain of generation of V1 neurons. A virtually complete loss of MN and V2 neurons is observed at cervical levels of the spinal cord. The generation of V3 neurons (and cranial visceral motor neurons at hindbrain levels) is unaffected by the loss of Nkx6.1 or by the ectopic expression of Dbx2.
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