Serotonergic neurons in the dorsal raphe (DR) nucleus are associated with several psychiatric disorders including depression and anxiety disorders, which often have a neurodevelopmental component. During embryonic development, GATA transcription factors GATA2 and GATA3 operate as serotonergic neuron fate selectors and regulate the differentiation of serotonergic neuron subtypes of DR. Here, we analyzed the requirement of GATA cofactor ZFPM1 in the development of serotonergic neurons using Zfpm1 conditional mouse mutants. Our results demonstrated that, unlike the GATA factors, ZFPM1 is not essential for the early differentiation of serotonergic precursors in the embryonic rhombomere 1. In contrast, in perinatal and adult male and female Zfpm1 mutants, a lateral subpopulation of DR neurons (ventrolateral part of the DR) was lost, whereas the number of serotonergic neurons in a medial subpopulation (dorsal region of the medial DR) had increased. Additionally, adult male and female Zfpm1 mutants had reduced serotonin concentration in rostral brain areas and displayed increased anxiety-like behavior. Interestingly, female Zfpm1 mutant mice showed elevated contextual fear memory that was abolished with chronic fluoxetine treatment. Altogether, these results demonstrate the importance of ZFPM1 for the development of DR serotonergic neuron subtypes involved in mood regulation. It also suggests that the neuronal fate selector function of GATAs is modulated by their cofactors to refine the differentiation of neuronal subtypes.

SIGNIFICANCE STATEMENT Predisposition to anxiety disorders has both a neurodevelopmental and a genetic basis. One of the brainstem nuclei involved in the regulation of anxiety is the dorsal raphe, which contains different subtypes of serotonergic neurons. We show that inactivation of a transcriptional cofactor ZFPM1 in mice results in a developmental failure of laterally located dorsal raphe serotonergic neurons and changes in serotonergic innervation of rostral brain regions. This leads to elevated anxiety-like behavior and contextual fear memory, alleviated by chronic fluoxetine treatment. Our work contributes to understanding the neurodevelopmental mechanisms that may be disturbed in the anxiety disorder.

背脊（DR）核中的血清素能神经元与多种精神疾病有关，包括抑郁症和焦虑症，这些疾病通常具有神经发育成分。在胚胎发育过程中，GATA转录因子GATA2和GATA3充当血清素能神经元命运的选择者，并调节DR的血清素能神经元亚型的分化。在这里，我们分析了使用Zfpm1条件小鼠突变体在血清素能神经元发育中GATA辅因子ZFPM1的需求。我们的结果表明，与GATA因子不同，ZFPM1对于胚胎菱形1的血清素能前体的早期分化不是必需的。相比之下，在围产期和成年男性和女性Zfpm1中突变体，DR神经元的外侧亚群（DR的腹外侧部分）丢失了，而内侧亚群（内侧DR的背侧区域）中的血清素能神经元的数量增加了。此外，成年男性和女性Zfpm1突变体降低了延髓脑区域的血清素浓度，并表现出了类似焦虑的行为。有趣的是，雌性Zfpm1突变小鼠表现出较高的情境恐惧记忆，而慢性氟西汀治疗则消除了这种记忆。总而言之，这些结果证明了ZFPM1对于参与情绪调节的DR血清素能神经元亚型发展的重要性。这也表明，GATAs的神经元命运选择器功能受到其辅助因子的调节，以改善神经元亚型的分化。

意义声明易患焦虑症具有神经发育和遗传基础。参与焦虑调节的脑干核之一是背缝，其中包含不同亚型的血清素能神经元。我们表明，在小鼠中转录辅因子ZFPM1的失活导致侧卧背背侧血清素能神经元的发育失败和延髓性脑区域的血清素能神经支配的变化。慢性氟西汀治疗减轻了焦虑症样行为和情境恐惧记忆。我们的工作有助于理解在焦虑症中可能受到干扰的神经发育机制。