Abstract
Engrailed-1 (En1) is expressed in the ventral ectoderm of the developing limb where it plays an instructive role in the dorsal-ventral patterning of the forelimb. Besides its well-described role as a transcription factor in regulating gene expression through its DNA-binding domain, En1 may also be secreted to form an extracellular gradient, and directly impact on the formation of the retinotectal map. We show here that absence of En1 causes mispatterning of the forelimb and thus defects in the dorsal-ventral pathfinding choice of motor axons in vivo. In addition, En1 but not En2 also has a direct and specific repulsive effect on motor axons of the lateral aspect of the lateral motor column (LMC) but not on medial LMC projections. Moreover, an ectopic dorsal source of En1 pushes lateral LMC axons to the ventral limb in vivo. Thus, En1 controls the establishment of limb innervation through two distinct molecular mechanisms.
Highlights
Execution of coordinated locomotor behaviors relies on precise assembly of circuits between central nervous system neurons and peripheral muscle fibers during embryonic development
Neurons innervating limb musculature are clustered in lateral motor columns (LMC) where neurons are organized in patterns that topographically reflect their peripheral targets: motor neurons in the medial aspect (LMCm) project to the ventral limb, while the lateral part (LMCl) consists of neurons innervating dorsal limb musculature [2,3,4]
Expression of En1 in the ventral limb ectoderm is essential for patterning, most likely by repressing dorsal differentiation programs induced by Wnt7a [7]
Summary
Execution of coordinated locomotor behaviors relies on precise assembly of circuits between central nervous system neurons and peripheral muscle fibers during embryonic development. Within the developing limb, a system of transcription factor codes is utilized for anterior-posterior, proximo-distal, and dorso-ventral patterning: Wnt7a, a secreted factor expressed by the dorsal limb ectoderm, triggers differentiation of dorsal mesenchymal structures by inducing expression of the dorsalizing LIM homeodomain-containing gene Lmx1b [5,6,7]. Mutation of En1 results in a partial dorsal transformation of the ventral paw and a ventro-proximal expansion of the apical ectodermal ridge (AER; [8]) Together, these transcriptional networks in limb and spinal cord control expression of guidance cues and their cognate axonal receptors, e.g. members of the ephrin-Eph family, which determine the specificity of spinal motor connectivity with corresponding limb musculature [11,12]. Our data establish that En1 critically and directly participates in the dorso-ventral guidance decision of motor nerves innervating the developing forelimb by two distinct mechanisms
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