During the first part of this opening lesson, students explore the characteristics of scientific models and their role in driving science inquiry. They also interpret a number of simple models of biological and chemical processes. In the second half of the lesson, students are introduced to the unit’s anchoring phenomenon through a series of videos depicting patients from different countries performing a motor task in a clinical setting. After watching the videos, students formulate questions based on their observations of the patients’ motor behavior and any prior knowledge of disorders affecting human movement. Students subsequently organize their questions into categories that define possible areas of investigation and exploration. Teachers then invite students to prioritize investigations. At the conclusion of the lesson, students create an initial explanatory model (v.1) that incorporates their observations and prior knowledge/experience. Teachers inform students that they will have multiple opportunities to revise their model based on the discoveries they make in later lessons. The final model (v.6) will be the target of summative assessment in the final lesson (L10).

After watching the clinical videos presented in Lesson 1, your students are likely to ask questions about the involvement of the nervous system or the muscular system in the abnormal movements displayed by the patients they observed. This lesson is aimed at building students’ foundational knowledge of these body systems. This knowledge will support them in their interpretation of storyline data that they encounter later in the unit. In the first part of this lesson, students explore the hierarchical organization of muscle tissue as a first step toward examining the process of muscle fiber activation, which converges on the sliding filament model of muscle contraction. In the second half of this lesson, students examine the process by which nerve cells within the motor cortex of the brain (upper motor neurons) activate spinal cord motor neurons (via the synapse) through a relatively simple pathway called the corticospinal tract. They also explore the process by which motor neurons in the spinal cord activate muscle fibers/cells to produce contraction (via the neuromuscular junction).

In this lesson, students analyze and interpret real clinical data obtained from patients using electromyelography, transcranial magnetic stimulation, and functional magnetic resonance imaging. By connecting this data with foundational information obtained in Lesson 2 and direct observations of the abnormal motor behavior displayed by patients (Lesson1), students discover that the movement disorder is likely to involve a failure of axons within the corticospinal tract to appropriately activate muscles. This possibility receives additional support in Lesson 6 by information that students obtain from data records that they access through the Online Mendelian Inheritance in Man database.

Because the movement disorder under study runs in families, some students are likely to implicate the involvement of genes in the observed motor phenotype. As they will discover in later lessons, mutations in genes involved in a key phase of nervous system development are linked to the corticospinal tract defect in patients affected by the movement disorder. This four-part lesson is intended to prepare students to explore how mutations in these genes can impair the formation of the corticospinal tract during human development. During this lesson, students explore the structure of chromosomes, the composition and organization of DNA, and the role that genes play in specifying the amino acid sequence, structure, and function of proteins used by cells to carry out essential life functions. Understanding this foundational information is required for students to later analyze, interpret, and connect evidence that links specific gene mutations and corresponding protein anomalies to the movement disorder.

In the opening lesson of this unit, students are likely to formulate questions about the disorder’s heritability. This lesson is intended to support students in addressing these important questions. During the first half of this lesson, students explore select examples of dominant and recessive gene alleles, their chromosomal positions and nucleotide sequences (using the NCBI Genome Data Viewer), and their role in the expression of a particular phenotype (trait). They then use Punnett squares to predict the probability that offspring will inherit a phenotype (trait) from their parents and pedigree charts to show actual patterns of inheritance through multiple generations of a family. Students then use information from semi-fictitious case reports of affected family members to deduce the pattern of inheritance (e.g., autosomal dominant). In the final part of this lesson, students use Phenomizer, a powerful web-based application within the Human Phenotype Ontology database, to diagnose the movement disorder. To perform the diagnosis, students select the disorder’s pattern of inheritance (obtained through pedigree analysis) and enter clinical features (symptoms) presented by affected patients (obtained from semi-fictitious case reports). The digital diagnosis report generated by the Phenomizer app not only includes the name of the disorder, but the name of genes linked to the disorder (which are hyperlinked to data records in the Online Mendelian Inheritance in Man database). The role of these genes in the movement disorder will be the focus of student exploration in subsequent lessons.

In this lesson, students navigate the Online Mendelian Inheritance in Man (OMIM) database to identify four genes linked to the movement disorder. This finding connects to a key discovery that students make in Lessons 4 and 5 (that the movement disorder is genetically heritable). By examining data records contained in the database, students discover that the proteins encoded by two of these four genes (NTN1 and DCC) physically interact during a key phase of nervous system development (axon pathfinding). The information that students encounter in OMIM data records also builds upon a key discovery made in Lesson 5, namely that the movement disorder results from a failure of axons within the corticospinal tract to appropriately cross the midline during nervous system development. The next several lessons are designed to help students understand how physical interactions between Netrin-1 (encoded by the NTN1 gene) and DCC proteins enable axons to cross the midline.

In Lesson 6, students used the Online Mendelian Inheritance in Man database to identify genes linked to the movement disorder. They also determined that the proteins encoded by two of these genes (Netrin-1 and DCC) interact and play important roles in axon pathfinding, a key phase of nervous system development. In L7A and L7B, students explore and interpret models depicting the preceding phases of nervous system development (neurogenesis, cell fate specification/cell differentiation) and then examine and interpret models of axon pathfinding, the process by which differentiated neurons locate target cells with which they will ultimately establish functional connections (synapses). As part of this exploration, students examine the architecture of the axon and its terminal growth cone, neuronal structures that play key roles in axon pathfinding. They also analyze models that highlight how growth cones display cell surface receptors that are capable of recognizing and steering the axon in response to secreted navigational cues distributed within the developing nervous system.

Our understanding of axon pathfinding is derived from the study of model vertebrates and invertebrates. In this lesson, students explore the concept of a model organism/system and the conservation of gene function across animal phyla. In L8A, students use the OpenWorm 3D modeling platform to examine and characterize the trajectories of wild-type C. elegans axons and make general comparisons to the pathway taken by the axons of upper (cortical) motor neurons that form the corticospinal tract in humans (e.g., axons in both systems cross the midline and travel significant distances before making contact with contralateral target cells). Students then examine how mutations in Unc-6 (the NTN1 ortholog) and Unc-40 (the C. elegans DCC ortholog) affect the pathways taken by axons that cross either the dorsal or ventral midline of the C. elegans body axis. In L8B, students interpret data that shows the trajectories of hindbrain axons in mice harboring mutations that affect the regional expression of the NTN1 gene.

In the previous lesson, students explored the trajectories of axons in model organisms (worm and mouse) that harbor mutations in either the NTN1 or DCC genes. By interpreting published data, students discover that in both organisms, mutations in either gene result in a failure of axons to cross the midline and project on the opposite (contralateral) side of the body axis (abnormal decussation). This observation connects to data encountered in Lessons 5 and 6. In Lesson 9A, students compare and evaluate diffusion tensor imaging (DTI) tractography data obtained from normal human subjects and individuals affected by the movement disorder. They discover that mutations in either NTN1 or DCC result in a partial failure of axons within the corticospinal tract to cross the CNS midline at the level of the hindbrain (abnormal corticospinal tract decussation). In Lessons 9B and C, students use online informatics tools and databases, most notably NCBI ClinVar, to examine NTN1 and DCC gene variations (mutations) and determine their impact on the amino acid sequence of the corresponding proteins. Students also use the Simple Modular Architecture Research Tool to explore how mutations impair the ability of Netrin-1 and DCC proteins to physically interact with one another and perform a role in guiding upper (cortical) motor neurons across the hindbrain midline during nervous system development.

At this point in the NeuroLab storyline, students will have implicated defects in the DCC axon guidance receptor or the Netrin-1 guidance signal as the primary cause of the movement disorder. In the first half of this concluding lesson, students use Brain Explorer 2 (a companion application of the Allen Developing Mouse Brain Atlas) to examine the spatial distribution of NTN1 and DCC mRNA in the developing mouse embryo and evaluate the extent to which this expression data is in agreement with the relevant components of their emerging explanatory model. In the second half of this lesson, students receive guidance on evaluating their model for the presence of different components (e.g., behavioral, anatomical, developmental, etc.). They are then invited to discuss and provide explanations for any unresolved questions or notable gaps in their explanatory models. The experience concludes by inviting students to propose a treatment for CMM based on their current understanding of the disorder

All unit resources (including Assessment Support, External Resources and Supplemental Materials)