The Role of Lmx1a and Lmx1b in Regulating Mesencephalon Development and Dopamine Neuron Specification

摘要

One of the most challenging questions in developmental biology is howneurons are specified, acquire their distinct characteristics and findtheir correct innervations to form functional circuits. The developmentof different subsets of neurons involves the expression of a programintrinsic to each cell type and the response to extrinsic environmentalinfluences represented by soluble factors. Breakthroughs in theunderstanding of the genetic programs that controls the specification ofventral cell fates in the spinal cord and hindbrain, have provided usefultools for the study of similar genetic networks in the more complexrostral regions of the central nervous system, such as the mesencephalon(also called midbrain).Midbrain dopamine (mDA) neurons are born in the ventral midline of themidbrain and regulate important functions in the brain, including motorcontrol, cognition, emotions and learning. The degeneration of mDAneurons is the major hallmark of Parkinson s disease (PD). The lack ofknowledge regarding the factors involving in the early specification ofmDA neurons has been one of the obstacles in applying embryonic stem cell(ESC)-based replacement therapy for PD. In paper I, we showed that Lmx1aand Msx1/2 are two key components in the development of mDA neurons.Lmx1a is necessary and sufficient for the acquisition of the proper mDAfate by activating the expression of downstream mDA neuron markers, whileMsx1/2 synergizes with Lmx1a by suppressing alternative cell fates andpromoting the progression of neurogenesis. Furthermore, we applied thisknowledge to ESCs and showed that forced expression of Lmx1a couldefficiently induce bona fide mDA neurons. In paper II, we continued toevaluate the role of Lmx1a in the mouse and compared the function ofLmx1a with its close homolog Lmx1b during mDA development. Surprisingly,loss of Lmx1a resulted in a moderate reduction of mDA neurons, which waspartly due to the delayed conversion of floor plate into a neurogenicregion at an early stage. Lmx1b could compensate to large extent for theloss of Lmx1a in mDA neuron generation as the compound genotype of theLmx1 genes displayed a dose-dependent effect. Importantly, we showed thatLmx1a and Lmx1b have distinct roles in specifying two subgroups, i.e.medial and lateral mDA neurons. In addition, we revealed the function ofLmx1b in patterning other ventral cell types, i.e. oculomotor (OM)neurons and red nucleus (RN) cells. Loss of Lmx1b caused a dramaticreduction of OM neurons. By contrast, RN cells were born prematurely andwere overproduced. Our current findings establish that Lmx1b influencesthe differentiation of multiple neuronal subtypes in the ventralmidbrain, while the activity of Lmx1a in the ventral midbrain appearsdevoted to the differentiation of mDA neurons.